Antidiabetic tricyclic compounds

ABSTRACT

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslip idemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a disease derived from multiple causative factorsand characterized by elevated levels of plasma glucose (hyperglycemia)in the fasting state or after administration of glucose during an oralglucose tolerance test. There are two generally recognized forms ofdiabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus(IDDM), patients produce little or no insulin, the hormone whichregulates glucose utilization. In Type 2 diabetes, ornoninsulin-dependent diabetes mellitus (NIDDM), insulin is stillproduced in the body. Patients having Type 2 diabetes have a resistanceto the effects of insulin in stimulating glucose and lipid metabolism inthe main insulin-sensitive tissues, which are muscle, liver and adiposetissues. These patients often have normal levels of insulin, and mayhave hyperinsulinemia (elevated plasma insulin levels), as theycompensate for the reduced effectiveness of insulin by secretingincreased amounts of insulin. Insulin resistance is not primarily causedby a diminished number of insulin receptors but rather by a post-insulinreceptor binding defect that is not yet completely understood. This lackof responsiveness to insulin results in insufficient insulin-mediatedactivation of uptake, oxidation and storage of glucose in muscle, andinadequate insulin-mediated repression of lipolysis in adipose tissueand of glucose production and secretion in the liver.

Persistent or uncontrolled hyperglycemia that occurs with diabetes isassociated with increased and premature morbidity and mortality. Oftenabnormal glucose homeostasis is associated both directly and indirectlywith obesity, hypertension, and alterations of the lipid, lipoproteinand apolipoprotein metabolism, as well as other metabolic andhemodynamic disease. Patients with Type 2 diabetes mellitus have asignificantly increased risk of macrovascular and microvascularcomplications, including atherosclerosis, coronary heart disease,stroke, peripheral vascular disease, hypertension, nephropathy,neuropathy, and retinopathy. Therefore, therapeutic control of glucosehomeostasis, lipid metabolism, obesity, and hypertension are criticallyimportant in the clinical management and treatment of diabetes mellitus.

Patients who have insulin resistance often have several symptoms thattogether are referred to as syndrome X, or the Metabolic Syndrome.According to one widely used definition, a patient having MetabolicSyndrome is characterized as having three or more symptoms selected fromthe following group of five symptoms: (1) abdominal obesity; (2)hypertriglyceridemia; (3) low high-density lipoprotein cholesterol(HDL); (4) high blood pressure; and (5) elevated fasting glucose, whichmay be in the range characteristic of Type 2 diabetes if the patient isalso diabetic. Each of these symptoms is defined clinically in the ThirdReport of the National Cholesterol Education Program Expert Panel onDetection, Evaluation and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III, or ATP III), National Institutes of Health,2001, NIH Publication No. 01-3670. Patients with Metabolic Syndrome,whether or not they have or develop overt diabetes mellitus, have anincreased risk of developing the macrovascular and microvascularcomplications that occur with Type 2 diabetes, such as atherosclerosisand coronary heart disease.

There are several available treatments for Type 2 diabetes, each ofwhich has its own limitations and potential risks. Physical exercise anda reduction in dietary intake of calories often dramatically improve thediabetic condition and are the usual recommended first-line treatment ofType 2 diabetes and of pre-diabetic conditions associated with insulinresistance. Compliance with this treatment is generally very poorbecause of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of fat andcarbohydrates. Pharmacologic treatments for diabetes have largelyfocused on three areas of pathophysiology: (1) hepatic glucoseproduction (biguanides, such as phenformin and metformin), (2) insulinresistance (PPAR agonists, such as rosiglitazone, troglitazone,engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512,LY-818 and pioglitazone), (3) insulin secretion (sulfonylureas, such astolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics(GLP-1 derivatives and analogs, such as exenatide and liraglitide); and(5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, suchas sitagliptin, alogliptin, vildagliptin, linagliptin, denagliptin, andsaxagliptin).

The biguanides are a class of drugs that are widely used to treat Type 2diabetes. The two best known biguanides, phenformin and metformin, causesome correction of hyperglycemia. The biguanides act primarily byinhibiting hepatic glucose production, and they also are believed tomodestly improve insulin sensitivity. The biguanides can be used asmonotherapy or in combination with other anti-diabetic drugs, such asinsulin or an insulin secretagogue, without increasing the risk ofhypoglycemia. However, phenformin and metformin can induce lacticacidosis and nausea/diarrhea. Metformin has a lower risk of side effectsthan phenformin and is widely prescribed for the treatment of Type 2diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer classof compounds that can ameliorate hyperglycemia and other symptoms ofType 2 diabetes. The glitazones that are currently marketed(rosiglitazone and pioglitazone) are agonists of the peroxisomeproliferator activated receptor (PPAR) gamma subtype. The PPAR-gammaagonists substantially increase insulin sensitivity in muscle, liver andadipose tissue in several animal models of Type 2 diabetes, resulting inpartial or complete correction of elevated plasma glucose levels withoutthe occurrence of hypoglycemia. PPAR-gamma agonism is believed to beresponsible for the improved insulin sensititization that is observed inhuman patients who are treated with the glitazones. New PPAR agonistsare currently being developed. Many of the newer PPAR compounds areagonists of one or more of the PPAR alpha, gamma and delta subtypes.Compounds that are agonists of both the PPAR alpha and PPAR gammasubtypes (PPAR alpha/gamma dual agonists) have been made and tested, butso far none have been approved by the regulatory authorities. Thecurrently marketed PPAR gamma agonists are modestly effective inreducing plasma glucose and HemoglobinA1C. The currently marketedcompounds do not greatly improve lipid metabolism and may actually havea negative effect on the lipid profile. Selective PPAR Gamma PartialAgonists (SPPARM's) are currently being developed and may be equallyeffective, with fewer side effects, such as weight gain and edema. Thus,the PPAR compounds represent an important advance in diabetic therapy.

Another widely used drug treatment involves the administration ofinsulin secretagogues, such as the sulfonylureas (e.g. tolbutamide,glipizide, and glimepiride). These drugs increase the plasma level ofinsulin by stimulating the pancreatic β-cells to secrete more insulin.Insulin secretion in the pancreatic β-cell is under strict regulation byglucose and an array of metabolic, neural and hormonal signals. Glucosestimulates insulin production and secretion through its metabolism togenerate ATP and other signaling molecules; whereas other extracellularsignals act as potentiators or inhibitors of insulin secretion throughGPCR's present on the plasma membrane. Sulfonylureas and related insulinsecretagogues act by blocking the ATP-dependent K+ channel in β-cells,which causes depolarization of the cell and the opening of thevoltage-dependent Ca2+ channels with stimulation of insulin release.This mechanism is non-glucose dependent, and hence insulin secretion canoccur regardless of the ambient glucose levels. This can cause insulinsecretion even if the glucose level is low, resulting in hypoglycemia,which can be fatal in severe cases. The administration of insulinsecretagogues must therefore be carefully controlled. The insulinsecretagogues are often used as a first-line drug treatment for Type 2diabetes.

Dipeptidyl peptidase IV (DPP-4) inhibitors (e.g., sitagliptin,vildagliptin, alogliptin, linagliptin, denagliptin, and saxagliptin)provide a new route for increasing insulin secretion in response to foodconsumption. DPP-4 is a cell surface protein with broad tissuedistribution that has been implicated in a wide range of biologicalfunctions. DPP-4 is identical to the T-cell activation marker CD26 andcan cleave a number of immunoregulatory, endocrine, and neurologicalpeptides in vitro. It is well established that the incretins GLP-1(glucagon-like peptide-1) and GIP (glucose-dependent insulinotropicpeptide; also known as gastric inhibitory peptide) stimulate insulinsecretion and are rapidly inactivated in vivo by DPP-4. These peptidylhormones are secreted by endocrine cells that are located in theepithelium of the small intestine. When these endocrine cells sense anincrease in the concentration of glucose in the lumen of the digestivetract, they act as the trigger for incretin release. Incretins arecarried through the circulation to beta cells in the pancreas and causethe beta cells to secrete more insulin in anticipation of an increase ofblood glucose resulting from the digesting meal. Studies withDPP-4(−/−)-deficient mice and clinical trials with DPP-4 inhibitorsindicate that DPP-4 inhibition increases the steady state concentrationsof GLP-1 and GIP, resulting in improved glucose tolerance. Inactivationof these peptides by DPP-4 may also play a role in glucose homeostasis.DPP-4 inhibitors therefore have utility in the treatment of Type 2diabetes and in the treatment and prevention of the numerous conditionsthat often accompany Type 2 diabetes, including Metabolic Syndrome,reactive hypoglycemia, and diabetic dyslipidemia. GLP-1 has othereffects that help to lower blood glucose and contribute to glucosehomeostasis. GLP-1 inhibits glucagon secretion from the liver. Glucagonis a hormone that increases blood glucose levels by stimulating glucoseproduction from glycogen stores in the liver. GLP-1 also delays stomachemptying, which helps to spread glucose absorption out over time, andthus limit hyperglycemia. Also, studies in animals have shown that GLP-1can increase the number of beta cells, either through promoting growthor by inhibiting apoptosis. Thus, potentiation of GLP-1 action bypreventing its degradation offers several mechanisms to attenuatehyperglycemia associated with Type 2 diabetes.

There has been a renewed focus on pancreatic islet-based insulinsecretion that is controlled by glucose-dependent insulin secretion.This approach has the potential for stabilization and restoration ofβ-cell function. In this regard, several orphan G-protein coupledreceptors (GPCR's) have recently been identified that are preferentiallyexpressed in the β-cell and that are implicated in glucose stimulatedinsulin secretion (GSIS). GPR40 is a cell-surface GPCR that is highlyexpressed in human (and rodent) islets as well as in insulin-secretingcell lines. Several naturally-occurring medium to long-chain fatty acids(FA's) as well as synthetic compounds, including several members of thethiazolidinedione class of PPARγ agonists, have recently been identifiedas ligands for GPR40 [Itoh, Y. et al., Nature, 422: 173 (2003); Briscoe,C. P. et al., J. Biol. Chem., 278: 11303 (2003); Kotarsky, K. et al.,Biochem. Biophys. Res. Comm, 301: 406 (2003)]. Under hyperglycemicconditions, GPR40 agonists are capable of augmenting the release ofinsulin from islet cells. The specificity of this response is suggestedby results showing that the inhibition of GPR40 activity by siRNAattenuates FA-induced amplification of GSIS. These findings indicatethat, in addition to the intracellular generation of lipid-derivativesof FA's that are thought to promote insulin release, FA's (and othersynthetic GPR40 agonists) may also act as extracellular ligands thatbind to GPR40 in mediating FA-induced insulin secretion.

There are several potential advantages of GPR40 as a potential targetfor the treatment of Type 2 diabetes. First, since GPR40-mediatedinsulin secretion is glucose dependent, there is little or no risk ofhypoglycemia. Second, the limited tissue distribution of GPR40 (mainlyin islets) suggests that there would be less chance for side effectsassociated with GPR40 activity in other tissues. Third, GPR40 agoniststhat are active in the islets may have the potential to restore orpreserve islet function. This would be highly advantageous, because longterm diabetes therapy often leads to the gradual diminution of isletactivity, so that after extended periods of treatment, it is oftennecessary to treat Type 2 diabetic patients with daily insulininjections. By restoring or preserving islet function, GPR40 agonistsmay delay or prevent the diminution and loss of islet function in a Type2 diabetic patient.

Compounds that are agonists of G-protein-coupled receptor 40 (GPR40) maybe useful to treat type 2 diabetes mellitus, obesity, hypertension,dyslipidemia, cancer, and metabolic syndrome, as well as cardiovasculardiseases, such as myocardial infarction and stroke, by improving glucoseand lipid metabolism and by reducing body weight. There is a need forpotent GPR40 agonists that have pharmacokinetic and pharmacodynamicproperties suitable for use as human pharmaceuticals.

Benzimidazole compounds are disclosed in WO 2010/051206; WO 2010/051176;WO 2010/047982; WO 2010/036613; WO 93/07124; WO 95/29897; WO 98/39342;WO 98/39343; WO 00/03997; WO 00/14095; WO 01/53272; WO 01/53291; WO02/092575; WO 02/40019; WO 03/018061; WO 05/002520; WO 05/018672; WO06/094209; U.S. Pat. No. 6,312,662; U.S. Pat. No. 6,489,476; US2005/0148643; DE 3 316 095; JP 6 298 731; EP 0 126 030; EP 0 128 862; EP0 129 506; and EP 0 120 403.

G-protein-coupled receptor 40 (GPR40) agonists are disclosed in WO2007/136572, WO 2007/136573, WO 2009/058237, WO 2006/083612, WO2006/083781, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO2010/091176, WO 2004/041266, EP 2004/1630152, WO 2004/022551, WO2005/051890, WO 2005/051373, EP 2004/1698624, WO 2005/086661, WO2007/213364, WO 2005/063729, WO 2005/087710, WO 2006/127503, WO2007/1013689, WO 2006/038738, WO 2007/033002, WO 2007/106469, WO2007/123225, WO 2008/001931, WO 2008/030618, WO 2008/054674, WO2008/054675, WO 2008/066097, WO 2008/130514, WO 2009/048527, WO2009/111056, WO 2010/045258, WO 2010/085522, WO 2010/085525, WO2010/085528, WO 2010/091176, WO 2010/143733 and WO 2012/0004187.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted compounds ofstructural formula I:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and embodiments thereof, are agonists ofG-protein-coupled receptor 40 (GPR40) and may be useful in thetreatment, prevention and suppression of diseases, disorders andconditions mediated by agonism of the G-protein-coupled receptor 40,such as Type 2 diabetes mellitus, insulin resistance, hyperglycemia,dyslipidemia, lipid disorders, obesity, hypertension, Metabolic Syndromeand atherosclerosis.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier. The present invention also relates to methods forthe treatment, control or prevention of disorders, diseases, andconditions that may be responsive to agonism of the G-protein-coupledreceptor 40 in a subject in need thereof by administering the compoundsand pharmaceutical compositions of the present invention. The presentinvention also relates to the use of compounds of the present inventionfor manufacture of a medicament useful in treating diseases, disordersand conditions that may be responsive to the agonism of theG-protein-coupled receptor 40. The present invention is also concernedwith treatment of these diseases, disorders and conditions byadministering the compounds of the present invention in combination witha therapeutically effective amount of another agent that may be usefulto treat the disease, disorder and condition. The invention is furtherconcerned with processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof; whereinA is phenyl;B is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

R¹ is selected from the group consisting of:

(1) halogen,

(2) —CN,

(3) —C₁₋₆alkyl,

(4) —(CH₂)_(r)—OC₁₋₆alkyl,

(5) —(CH₂)—C₃₋₆cycloalkyl, and

(6) —(CH₂)_(r)—O—(CH₂)_(r)—C₃₋₆cycloalkyl,

wherein each CH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromhalogen, —C₁₋₆alkyl and —(CH₂)_(v)—C₃₋₆cycloalkyl;R² is halogen;R³ when present is selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl, and

(3) —(CH₂)_(u)—C₃₋₆cycloalkyl,

wherein each C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen;R⁴ is selected from:

(1) —OC₁₋₆alkyl, and

(2) —C₁₋₆alkyl,

wherein —C₁₋₆alkyl is unsubstituted or substituted with one, two, threeor four substituents selected from R⁵;R⁵ is selected from the group consisting of:

(1) —(CH₂)_(s)halogen,

(2) —C₁₋₆alkyl,

(3) —(CH₂)_(s)—O—C₁₋₆alkyl,

(4) —(CH₂)_(s)OH,

(5) —(CH₂)_(s)SO₂C₁₋₆alkyl,

(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,

(7) —(CH₂)_(s)C₃₋₆cycloalkyl,

(8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH;Y is selected from:

(1) —CH(OH)—,

(2) —C(C₁₋₆alkyl)(OH)—,

(3) —C[(CH₂)_(t)—C₃₋₆cycloalkyl](OH)—,

(4) O,

(5) S, and

(6) SO₂,

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH;Z is selected from:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —(CH₂)_(s)—O—C₁₋₆alkyl,

(4) —(CH₂)_(s)—OH,

(5) —(CH₂)_(s)SO₂C₁₋₆alkyl,

(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,

(7) —(CH₂)_(s)C₃₋₆cycloalkyl, and

(8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen;m is 0, 1, 2 or 3;n is 1 or 2;p is 0, 1, 2 or 3;q is 0, 1, 2 or 3, provided that p+q is at least 2;r is 0, 1, 2 or 3;s is 0, 1, 2 or 3;t is 0, 1, 2 or 3;u is 0, 1, 2 or 3;v is 0, 1, 2 or 3; andw is 0, 1, 2 or 3.

In another embodiment, the present invention is concerned with novelcompounds of structural Formula I:

or a pharmaceutically acceptable salt thereof; whereinA is phenyl;B is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

R¹ is selected from the group consisting of:

(1) halogen,

(2) —CN,

(3) —C₁₋₆alkyl,

(4) —(CH₂)_(r)—OC₁₋₆alkyl,

(5) —(CH₂)_(r)—C₃₋₆cycloalkyl, and

(6) —(CH₂)_(r)—O—(CH₂)_(r)—C₃₋₆cycloalkyl,

wherein each CH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromhalogen, —C₁₋₆alkyl and —(CH₂)—C₃₋₆cycloalkyl;R² is halogen;R³ when present is selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl, and

(3) —(CH₂)_(u)—C₃₋₆cycloalkyl,

wherein each C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen;R⁴ is —OC₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted or substitutedwith one, two, three or four substituents selected from R⁵;R⁵ is selected from the group consisting of:

(1) —(CH₂)_(s)halogen,

(2) —C₁₋₆alkyl,

(3) —(CH₂)_(s)—O—C₁₋₆alkyl,

(4) —(CH₂)_(s) OH,

(5) —(CH₂)_(s)SO₂C₁₋₆alkyl,

(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,

(7) —(CH₂)_(s)C₃₋₆cycloalkyl,

(8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and—(CH₂)_(w)OH;Y is selected from:

(1) —CH(OH)—,

(2) —C(C₁₋₆alkyl)(OH)—,

(3) —C[(CH₂)_(t)—C₃₋₆cycloalkyl](OH)—,

(4) O,

(5) S, and

(6) SO₂,

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH;Z is selected from:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —(CH₂)_(s)—O—C₁₋₆alkyl,

(4) —(CH₂)_(s)—OH,

(5) —(CH₂)_(s)SO₂C₁₋₆alkyl,

(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,

(7) —(CH₂)_(s)C₃₋₆cycloalkyl, and

(8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen;m is 0, 1, 2 or 3;n is 1 or 2;p is 0, 1, 2 or 3;q is 0, 1, 2 or 3, provided that p+q is at least 2;r is 0, 1, 2 or 3;s is 0, 1, 2 or 3;t is 0, 1, 2 or 3;u is 0, 1, 2 or 3;v is 0, 1, 2 or 3; andw is 0, 1, 2 or 3.

The invention has numerous embodiments, which are summarized below. Theinvention includes the compounds as shown, and also includes individualdiastereoisomers, enantiomers, and epimers of the compounds, andmixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment of the present invention, A is phenyl. In a class ofthis embodiment, A is phenyl, wherein phenyl is substituted with one ortwo substituents selected from R¹, and wherein phenyl is substitutedwith one substituent selected from R². In another class of thisembodiment, A is phenyl, wherein phenyl is substituted with twosubstituents selected from R¹, and wherein phenyl is substituted withone substituent selected from R².

In another class of this embodiment, A is phenyl, wherein phenyl issubstituted with one substituent selected from R¹, and wherein phenyl issubstituted with one substituent selected from R².

In another embodiment of the present invention, A is

In another embodiment of the present invention, A is

In another embodiment of the present invention, A is

In another embodiment of the present invention, A is

In another embodiment of the present invention, B is selected from thegroup consisting of: phenyl and pyridyl. In another embodiment of thepresent invention, B is selected from phenyl and pyridyl, wherein phenyland pyridyl are substituted with R⁴, and are unsubstituted orsubstituted with one, two or three substituents selected from R³. In aclass of this embodiment of the present invention, B is selected fromphenyl and pyridyl, wherein phenyl and pyridyl are substituted with R⁴,and are unsubstituted or substituted with one or two substituentsselected from R³. In another class of this embodiment of the presentinvention, B is selected from phenyl and pyridyl, wherein phenyl andpyridyl are substituted with R⁴, and are unsubstituted or substitutedwith one substituent selected from R³. In another class of thisembodiment of the present invention, B is selected from phenyl andpyridyl.

In another embodiment of the present invention, B is pyridyl, whereinpyridyl is substituted with R⁴, and is unsubstituted or substituted withone, two or three substituents selected from R³. In a class of thisembodiment of the present invention, B is pyridyl, wherein pyridyl issubstituted with R⁴, and is unsubstituted or substituted with one or twosubstituents selected from R³. In another class of this embodiment ofthe present invention, B is pyridyl, wherein pyridyl is substituted withR⁴, and is unsubstituted or substituted with one substituent selectedfrom R³. In another class of this embodiment of the present invention, Bis pyridyl.

In another embodiment of the present invention, B is phenyl, whereinphenyl is substituted with R⁴, and is unsubstituted or substituted withone, two or three substituents selected from R³. In a class of thisembodiment of the present invention, B is phenyl, wherein phenyl issubstituted with R⁴, and is unsubstituted or substituted with one or twosubstituents selected from R³. In another class of this embodiment ofthe present invention, B is phenyl, wherein phenyl is substituted withR⁴, and is unsubstituted or substituted with one substituent selectedfrom R³. In another class of this embodiment of the present invention, Bis phenyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: halogen, —CN, —C₁₋₆alkyl, —(CH₂)_(r)—OC₁₋₆alkyl,—(CH₂)_(r)—C₃₋₆cycloalkyl, and —(CH₂)_(r)—O—(CH₂)—C₃₋₆cycloalkyl,wherein each CH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromhalogen, —C₁₋₆alkyl and —(CH₂)_(v)—C₃₋₆cycloalkyl. In a class of thisembodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromCl and F. In another class of this embodiment, each —C₁₋₆alkyl,—OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted or substituted with oneto four substituents selected from Cl. In another class of thisembodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromF.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: halogen, —CN, —C₁₋₆alkyl, —(CH₂)_(r)—OC₁₋₆alkyl,—(CH₂)_(r)—C₃₋₆cycloalkyl, and —(CH₂)_(r)—O—(CH₂)—C₃₋₆cycloalkyl,wherein each CH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromhalogen. In a class of this embodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyl and—C₃₋₆cycloalkyl is unsubstituted or substituted with one to foursubstituents selected from Cl and F. In another class of thisembodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl isunsubstituted or substituted with one to four substituents selected fromCl. In another class of this embodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyland —C₃₋₆cycloalkyl is unsubstituted or substituted with one to foursubstituents selected from F.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: halogen, —CN, —C₁₋₆alkyl, —OC₁₋₆alkyl and—C₃₋₆cycloalkyl, wherein each —C₁₋₆alkyl, —OC₁₋₆alkyl and—C₃₋₆cycloalkyl is unsubstituted or substituted with one to foursubstituents selected from halogen. In a class of this embodiment, each—C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to four substituents selected from Cl and F. Inanother class of this embodiment, each —C₁₋₆alkyl, —OC₁₋₆alkyl and—C₃₋₆cycloalkyl is unsubstituted or substituted with one to foursubstituents selected from Cl. In another class of this embodiment, each—C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to four substituents selected from F.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: halogen and —C₁₋₆alkyl, wherein —C₁₋₆alkyl isunsubstituted or substituted with one to four substituents selected fromhalogen. In a class of this embodiment, —C₁₋₆alkyl is unsubstituted orsubstituted with one to four substituents selected from Cl and F. Inanother class of this embodiment, —C₁₋₆alkyl is unsubstituted orsubstituted with one to four substituents selected from Cl. In anotherclass of this embodiment, —C₁₋₆alkyl is unsubstituted or substitutedwith one to four substituents selected from F.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: halogen and —C₁₋₆alkyl, wherein each —C₁₋₆alkyl isunsubstituted or substituted with one, two or three substituentsselected from halogen. In a class of this embodiment, each —C₁₋₆alkyl isunsubstituted or substituted with one, two or three substituentsselected from Cl and F. In another class of this embodiment, each—C₁₋₆alkyl is unsubstituted or substituted with one, two or threesubstituents selected from Cl. In another class of this embodiment, each—C₁₋₆alkyl is unsubstituted or substituted with one, two or threesubstituents selected from F. In another class of this embodiment, each—C₁₋₆alkyl is substituted with one, two or three substituents selectedfrom Cl and F. In another class of this embodiment, each —C₁₋₆alkyl issubstituted with one, two or three substituents selected from Cl. Inanother class of this embodiment, each —C₁₋₆alkyl is substituted withone, two or three substituents selected from F.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of: F, Cl, CF₃, and CHF₂. In another embodiment of thepresent invention, R¹ is selected from the group consisting of: F andCF₃. In another embodiment of the present invention, R¹ is halogen. In aclass of this embodiment, R¹ is selected from F and Cl. In another classof this embodiment, R¹ is Cl. In another class of this embodiment, R¹ isF.

In another embodiment of the present invention, R¹ is —C₁₋₆alkyl,wherein each —C₁₋₆alkyl is substituted with one, two or threesubstituents selected from halogen. In a class of this embodiment, R¹ is—C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted or substituted with one,two or three substituents selected from Cl and F. In another class ofthis embodiment, R¹ is —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstitutedor substituted with one, two or three substituents selected from Cl. Inanother class of this embodiment, R¹ is —C₁₋₆alkyl, wherein —C₁₋₆alkylis unsubstituted or substituted with one, two or three substituentsselected from F.

In another class of this embodiment, R¹ is —C₁₋₆alkyl, wherein—C₁₋₆alkyl is substituted with one, two or three substituents selectedfrom Cl and F. In another class of this embodiment, R¹ is —C₁₋₆alkyl,wherein —C₁₋₆alkyl is substituted with one, two or three substituentsselected from Cl. In another class of this embodiment, R¹ is —C₁₋₆alkyl,wherein —C₁₋₆alkyl is substituted with one, two or three substituentsselected from F.

In another embodiment of the present invention, R¹ is —CF₃ or —CHF₂. Inanother embodiment of the present invention, R¹ is —CF₃. In anotherembodiment of the present invention, R¹ is —CHF₂.

In another embodiment of the present invention, R² is halogen. Inanother embodiment of the present invention, R² is selected from: Br, I,F and Cl. In another embodiment of the present invention, R² is selectedfrom F and Cl. In another embodiment of the present invention, R² is F.In another embodiment of the present invention, R² is Cl.

In another embodiment of the present invention, R³ when present isselected from the group consisting of: halogen, and —C₁₋₆alkyl, whereineach C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen. In another embodiment of the presentinvention, R³ when present is selected from the group consisting of:halogen, and —C₁₋₆alkyl. In another embodiment of the present invention,R³ when present is selected from the group consisting of: F, Cl, CH₃,and CHF₂. In another embodiment of the present invention, R³ whenpresent is selected from the group consisting of: F and CH₃.

In another embodiment of the present invention, R³ when present isselected from the group consisting of: halogen, —C₁₋₆alkyl and—(CH₂)_(u)—C₃₋₆cycloalkyl, wherein each C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom halogen. In another embodiment of the present invention, R³ whenpresent is selected from the group consisting of: halogen, —C₁₋₆alkyl,and —C₃₋₆cycloalkyl, wherein each C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom halogen. In a class of this embodiment, each C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom Cl and F. In another class of this embodiment, each C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom Cl. In another class of this embodiment, each C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom F.

In another embodiment of the present invention, R³ when present isselected from the group consisting of: halogen, and —C₁₋₆alkyl, whereineach C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen. In a class of this embodiment, eachC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from Cl and F. In another class of this embodiment, eachC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from Cl. In another class of this embodiment, each C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom F.

In another embodiment of the present invention, R³ when present isselected from the group consisting of: F, —CF₃, —CHF₂, and —CH₃. Inanother embodiment of the present invention, R³ is selected from thegroup consisting of: F, —CF₃, —CHF₂, and —CH₃.

In another embodiment of the present invention, R³ is halogen. In aclass of this embodiment, R³ is selected from Cl and F. In another classof this embodiment, R³ is Cl. In another class of this embodiment, R³ isF.

In another embodiment of the present invention, R³ is —C₁₋₆alkyl,wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen. In a class of this embodiment, eachC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from Cl and F. In another class of this embodiment, eachC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from Cl. In another class of this embodiment, each C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom F.

In another embodiment of the present invention, R³ is —C₁₋₆alkyl. Inanother embodiment of the present invention, R³ is —C₁₋₆alkyl, whereineach C₁₋₆alkyl is substituted with one to three substituents selectedfrom halogen. In a class of this embodiment, each C₁₋₆alkyl issubstituted with one to three substituents selected from Cl and F. Inanother class of this embodiment, each C₁₋₆alkyl is substituted with oneto three substituents selected from Cl. In another class of thisembodiment, each C₁₋₆alkyl is substituted with one to three substituentsselected from F.

In another embodiment of the present invention, R³ when present isselected from the group consisting of: —CF₃, —CHF₂, and —CH₃. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of: —CF₃, —CHF₂, and —CH₃. In another embodiment of thepresent invention, R³ is —CF₃. In another embodiment of the presentinvention, R³ is —CHF₂. In another embodiment of the present invention,R³ is —CH₃.

In another embodiment of the present invention, R⁴ is selected from:—OC₁₋₆alkyl, and —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with one, two, three or four substituents selected from R⁵.In another embodiment of the present invention, R⁴ is selected from:—O—(CH₂)₂CH(OH)(C(CH₃)₂OH), —O—(CH₂)₂C(OH)(CH₃)CH₂OH,—O—CH₂CH(C(CH₃)₂OH)₂, —(CH₂)₂C(OH)(CH₃)CH₂OH, —O—(CH₂)₂CH(OH)CH₂OH,—O—(CH₂)₂C(OH)(CH₃)CH₃, —O—(CH₂)₃SO₂CH₃, —O—(CH₂)₂C(CH₃)₂OH,—O—(CH₂)₂C(OH)(CH₃)CHF₂, and —O—(CH₂)₂-oxetane-OH. In another embodimentof the present invention, R⁴ is selected from:—O—(CH₂)₂CH(OH)(C(CH₃)₂OH), —O—(CH₂)₂C(OH)(CH₃)CH₂OH,—O—CH₂CH(C(CH₃)₂OH)₂, —O—(CH₂)₂CH(OH)CH₂OH, —O—(CH₂)₂C(OH)(CH₃)CH₃,—O—(CH₂)₃SO₂CH₃, —O—(CH₂)₂C(CH₃)₂OH, —O—(CH₂)₂C(OH)(CH₃)CHF₂, and—O—(CH₂)₂-oxetane-OH. In another embodiment of the present invention, R⁴is selected from the group consisting of: —O—(CH₂)₂C(OH)(CH₃)CH₂OH,—O—(CH₂)₂C(CH₃)₂OH, and —O—(CH₂)₂C(OH)(CH₃)CHF₂. In another embodimentof the present invention, R⁴ is —(CH₂)₂C(OH)(CH₃)CH₂OH.

In another embodiment of the present invention R⁴ is —C₁₋₆alkyl, wherein—C₁₋₆alkyl is unsubstituted or substituted with one, two, three or foursubstituents selected from R⁵. In another embodiment of the presentinvention R⁴ is —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with three substituents selected from R⁵. In anotherembodiment of the present invention R⁴ is —C₄alkyl, wherein —C₄alkyl isunsubstituted or substituted with three substituents selected from R⁵.

In another embodiment of the present invention, R⁴ is —OC₁₋₆alkyl,wherein —C₁₋₆alkyl is unsubstituted or substituted with one, two, threeor four substituents selected from R⁵. In another embodiment of thepresent invention, R⁴ is —OC₁₋₆alkyl. In another embodiment of thepresent invention, R⁴ is —OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substitutedwith one, two, three or four substituents selected from R⁵. In anotherembodiment of the present invention, R⁴ is —OC₁₋₆alkyl, wherein—C₁₋₆alkyl is substituted with one, two or three substituents selectedfrom R⁵. In another embodiment of the present invention, R⁴ is—OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one or twosubstituents selected from R⁵. In another embodiment of the presentinvention, R⁴ is —OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with onesubstituent selected from R⁵. In another embodiment of the presentinvention, R⁴ is —OC₁₋₃alkyl, wherein —C₁₋₃alkyl is substituted with onesubstituent selected from R⁵. In another embodiment of the presentinvention, R⁴ is —OC₂₋₃alkyl, wherein —C₂₋₃alkyl is substituted with onesubstituent selected from R⁵. In another embodiment of the presentinvention, R⁴ is —OC₂alkyl, wherein —C₂alkyl is substituted with onesubstituent selected from R⁵. In another embodiment of the presentinvention, R⁴ is —OC₃alkyl, wherein —C₃alkyl is substituted with onesubstituent selected from R⁵.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —(CH₂)_(s)halogen, —C₁₋₆alkyl,—(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)OH, —(CH₂)_(s)SO₂C₁₋₆alkyl,—(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, —(CH₂)_(s)C₃₋₆cycloalkyl,—(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and—(CH₂)_(w)OH. In a class of this embodiment, each CH₂, C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from halogen. In a class of this embodiment, eachCH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted or substituted withone to three substituents selected from Cl and F. In another class ofthis embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstitutedor substituted with one to three substituents selected from Cl. Inanother class of this embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkylis unsubstituted or substituted with one to three substituents selectedfrom F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —(CH₂)_(s)halogen, —C₁₋₆alkyl,—(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)OH, —(CH₂)_(s)SO₂C₁₋₆alkyl,—(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, —(CH₂)_(s)C₃₋₆cycloalkyl,—(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen. In aclass of this embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom Cl and F. In another class of this embodiment, each CH₂, C₁₋₆alkyland C₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from Cl. In another class of this embodiment, eachCH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted or substituted withone to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —C₁₋₆alkyl, —(CH₂)_(s)OH, —(CH₂)_(s)SO₂C₁₋₆alkyl,—(CH₂)_(s)halogen, —(CH₂)_(s)OC₁₋₆alkyl, —(CH₂)_(s)C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and—(CH₂)_(w)OH. In a class of this embodiment, each CH₂, C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from Cl and F. In another class of thisembodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from Cl. In anotherclass of this embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —C₁₋₆alkyl, —(CH₂)_(s)OH, —(CH₂)_(s)SO₂C₁₋₆alkyl,—(CH₂)_(s)halogen, —(CH₂)_(s)OC₁₋₆alkyl, —(CH₂)_(s)C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen. In aclass of this embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom Cl and F. In another class of this embodiment, each CH₂, C₁₋₆alkyland C₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from Cl. In another class of this embodiment, eachCH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted or substituted withone to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —C₁₋₆alkyl, —(CH₂)_(s)OH, —(CH₂)_(s)SO₂C₁₋₆alkyl,and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen. In a class of thisembodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substituted withone to three substituents selected from Cl and F. In another class ofthis embodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substitutedwith one to three substituents selected from Cl. In another class ofthis embodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substitutedwith one to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: halogen, —C₁₋₆alkyl, —OH, —SO₂C₁₋₆alkyl, and

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: F, —CH₃, —OH, —SO₂CH₃, and

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: F, —CH₃, —OH, —SO₂CH₃, and

and wherein Y is oxygen, Z is —OH, p is 1 and q is 1.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —C₁₋₆alkyl, —OH, —SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen. In a class of thisembodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substituted withone to three substituents selected from Cl and F. In another class ofthis embodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substitutedwith one to three substituents selected from Cl. In another class ofthis embodiment, each CH₂ and C₁₋₆alkyl is unsubstituted or substitutedwith one to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —CH₃, —OH, —SO₂CH₃, and

wherein each CH₃ and CH₂ is unsubstituted or substituted with one tothree substituents selected from halogen. In a class of this embodiment,each CH₃ and CH₂ is unsubstituted or substituted with one to threesubstituents selected from Cl and F. In another class of thisembodiment, each CH₃ and CH₂ is unsubstituted or substituted with one tothree substituents selected from Cl. In another class of thisembodiment, each CH₃ and CH₂ is unsubstituted or substituted with one tothree substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of: —C₁₋₆alkyl, and —(CH₂)_(s)OH, wherein each CH₂ andC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from halogen. In a class of this embodiment, R⁵ is selectedfrom the group consisting of: —CH₃ and —OH, wherein each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom halogen. In another class of this embodiment, each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom Cl and F. In another class of this embodiment, each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom Cl. In another class of this embodiment, each CH₃ is unsubstitutedor substituted with one to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from:—(CH₂)_(s)SO₂C₁₋₆alkyl, wherein each CH₂ and C₁₋₆alkyl is unsubstitutedor substituted with one to three substituents selected from halogen. Ina class of this embodiment, R⁵ is —SO₂CH₃, wherein each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom halogen. In another class of this embodiment, each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom Cl and F. In another class of this embodiment, each CH₃ isunsubstituted or substituted with one to three substituents selectedfrom Cl. In another class of this embodiment, each CH₃ is unsubstitutedor substituted with one to three substituents selected from F.

In another embodiment of the present invention, R⁵ is selected from thegroup consisting of:

wherein each CH₂ is unsubstituted or substituted with one to threesubstituents selected from halogen. In a class of this embodiment, R⁵ is

wherein each CH₂ is unsubstituted or substituted with one to threesubstituents selected from halogen. In another class of this embodiment,each CH₂ is unsubstituted or substituted with one to three substituentsselected from Cl and F. In another class of this embodiment, each CH₂ isunsubstituted or substituted with one to three substituents selectedfrom Cl. In another class of this embodiment, each CH₂ is unsubstitutedor substituted with one to three substituents selected from F.

In another embodiment of the present invention, Y is selected from:—CH(OH)—, —C(C₁₋₆alkyl)(OH)—, —C[(CH₂)_(t)—C₃₋₆cycloalkyl](OH)—, O, Sand SO₂, wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstitutedor substituted with one to three substituents selected from halogen and(CH₂)_(w)OH. In a class of this embodiment, each CH₂, C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from halogen. In another class of this embodiment,each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted or substitutedwith one to three substituents selected from Cl and F. In another classof this embodiment, each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl isunsubstituted or substituted with one to three substituents selectedfrom Cl. In another class of this embodiment, each CH₂, C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from F.

In another embodiment of the present invention, Y is selected from:—CH(OH)—, —C(CH₃)(OH)—, O, S and SO₂, wherein each CH₃ is unsubstitutedor substituted with one to three substituents selected from halogen and(CH₂)_(w)OH. In a class of this embodiment, each CH₃ is unsubstituted orsubstituted with one to three substituents selected from halogen. Inanother class of this embodiment, each CH₃ is unsubstituted orsubstituted with one to three substituents selected from Cl and F. Inanother class of this embodiment, each CH₃ is unsubstituted orsubstituted with one to three substituents selected from Cl. In anotherclass of this embodiment, each CH₃ is unsubstituted or substituted withone to three substituents selected from F.

In another embodiment of the present invention, Y is selected from:—CH(OH)—, —C(CH₃)(OH)—, O, S, and SO₂. In another embodiment of thepresent invention, Y is selected from: —CH(OH)— and —C(CH₃)(OH)—. Inanother embodiment of the present invention, Y is selected from: O, Sand SO₂. In another embodiment of the present invention, Y is selectedfrom: S and SO₂. In another embodiment of the present invention, Y issulfur. In another embodiment of the present invention, Y is SO₂. Inanother embodiment of the present invention, Y is oxygen.

In another embodiment of the present invention, Z is selected from:hydrogen, —C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)—OH,—(CH₂)_(s)SO₂C₁₋₆alkyl, —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,—(CH₂)_(s)C₃₋₆cycloalkyl, and —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen.

In another embodiment of the present invention, Z is selected from:—C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)—OH,—(CH₂)_(s)SO₂C₁₋₆alkyl, —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl,—(CH₂)_(s)C₃₋₆cycloalkyl, and —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen.

In another embodiment of the present invention, Z is selected from:hydrogen, —C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)—OH and—(CH₂)_(s)C₃₋₆cycloalkyl, wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkylis unsubstituted or substituted with one to three substituents selectedfrom halogen.

In another embodiment of the present invention, Z is selected from:—C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl, —(CH₂)_(s)—OH and—(CH₂)_(s)C₃₋₆cycloalkyl, wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkylis unsubstituted or substituted with one to three substituents selectedfrom halogen.

In another embodiment of the present invention, Z is selected from:hydrogen, —C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl and —(CH₂)_(s)—OH, whereineach CH₂, and C₁₋₆alkyl is unsubstituted or substituted with one tothree substituents selected from halogen.

In another embodiment of the present invention, Z is selected from:—C₁₋₆alkyl, —(CH₂)_(s)—O—C₁₋₆alkyl and —(CH₂)_(s)—OH, wherein each CH₂,and C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen.

In another embodiment of the present invention, Z is selected from:hydrogen, —C₁₋₆alkyl, and —(CH₂)_(s)—OH, wherein each CH₂, and C₁₋₆alkylis unsubstituted or substituted with one to three substituents selectedfrom halogen.

In another embodiment of the present invention, Z is selected from:—C₁₋₆alkyl, and —(CH₂)₅—OH, wherein each CH₂, and C₁₋₆alkyl isunsubstituted or substituted with one to three substituents selectedfrom halogen.

In another embodiment of the present invention, Z is hydrogen.

In another embodiment of the present invention, Z is selected from:—C₁₋₆alkyl, wherein C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen.

In another embodiment of the present invention, Z is selected from—(CH₂)_(s)—OH, wherein each CH₂ is unsubstituted or substituted with oneto three substituents selected from halogen. In another embodiment ofthe present invention, Z is selected from —(CH₂)_(s)—OH. In anotherembodiment of the present invention, Z is —OH.

In another embodiment of the present invention, m is 0, 1, 2 or 3. Inanother embodiment of the present invention, m is 0, 1 or 2. In anotherembodiment of the present invention, m is 0, 1 or 3. In anotherembodiment of the present invention, m is 0, 2 or 3. In anotherembodiment of the present invention, m is 0 or 2. In another embodimentof the present invention, m is 0 or 1. In another embodiment of thepresent invention, m is 0 or 3. In another embodiment of the presentinvention, m is 1, 2 or 3. In another embodiment of the presentinvention, m is 1 or 3. In another embodiment of the present invention,m is 1 or 2. In another embodiment of the present invention, m is 0. Inanother embodiment of the present invention, m is 1. In anotherembodiment of the present invention, m is 2. In another embodiment ofthe present invention, m is 3.

In another embodiment of the present invention, n=1 or 2. In anotherembodiment of the present invention, n is 1. In another embodiment ofthe present invention, n is 2.

In another embodiment of the present invention, p=0, 1, 2 or 3. Inanother embodiment of the present invention, p is 0, 1 or 2. In anotherembodiment of the present invention, p is 0, 1 or 3. In anotherembodiment of the present invention, p is 0, 2 or 3. In anotherembodiment of the present invention, p is 0 or 2. In another embodimentof the present invention, p is 0 or 1. In another embodiment of thepresent invention, p is 0 or 3. In another embodiment of the presentinvention, p is 1, 2 or 3. In another embodiment of the presentinvention, p is 1 or 3. In another embodiment of the present invention,p is 1 or 2. In another embodiment of the present invention, p is 2 or3. In another embodiment of the present invention, p is 0. In anotherembodiment of the present invention, p is 1. In another embodiment ofthe present invention, p is 2. In another embodiment of the presentinvention, p is 3.

In another embodiment of the present invention, q=0, 1, 2 or 3. Inanother embodiment of the present invention, q is 0, 1 or 2. In anotherembodiment of the present invention, q is 0, 1 or 3. In anotherembodiment of the present invention, q is 0, 2 or 3. In anotherembodiment of the present invention, q is 0 or 2. In another embodimentof the present invention, q is 0 or 1. In another embodiment of thepresent invention, q is 0 or 3. In another embodiment of the presentinvention, q is 1, 2 or 3. In another embodiment of the presentinvention, q is 1 or 3. In another embodiment of the present invention,q is 1 or 2. In another embodiment of the present invention, q is 2 or3. In another embodiment of the present invention, q is 0. In anotherembodiment of the present invention, q is 1. In another embodiment ofthe present invention, q is 2. In another embodiment of the presentinvention, q is 3.

In another embodiment p+q is at least 2. In another embodiment, p+q is 2or greater. In another embodiment, p+q is 2, 3, 4, 5 or 6. In anotherembodiment, p is 1 and q is 1. In another embodiment, p is 0 and q is 2.In another embodiment, p is 2 and q is 0. In another embodiment, p is 2and q is 1. In another embodiment, p is 1 and q is 2. In anotherembodiment p is 2 and q is 2. In another embodiment, p is 3 and q is 2.In another embodiment, p is 2 and q is 3. In another embodiment, p is 3and q is 3. In another embodiment, p is 0 and q is 3. In anotherembodiment, p is 3 and q is 0. In another embodiment, p is 1 and q is 3.In another embodiment, p is 3 and q is 1.

In another embodiment of the present invention, r=0, 1, 2 or 3. Inanother embodiment of the present invention, r is 0, 1 or 2. In anotherembodiment of the present invention, r is 0, 1 or 3. In anotherembodiment of the present invention, r is 0, 2 or 3. In anotherembodiment of the present invention, r is 0 or 2. In another embodimentof the present invention, r is 0 or 1. In another embodiment of thepresent invention, r is 0 or 3. In another embodiment of the presentinvention, r is 1, 2 or 3. In another embodiment of the presentinvention, r is 1 or 3. In another embodiment of the present invention,r is 1 or 2. In another embodiment of the present invention, r is 2 or3. In another embodiment of the present invention, r is 0. In anotherembodiment of the present invention, r is 1. In another embodiment ofthe present invention, r is 2. In another embodiment of the presentinvention, r is 3.

In another embodiment of the present invention, s=0, 1, 2 or 3. Inanother embodiment of the present invention, s is 0, 1 or 2. In anotherembodiment of the present invention, s is 0, 1 or 3. In anotherembodiment of the present invention, s is 0, 2 or 3. In anotherembodiment of the present invention, s is 0 or 2. In another embodimentof the present invention, s is 0 or 1. In another embodiment of thepresent invention, s is 0 or 3. In another embodiment of the presentinvention, s is 1, 2 or 3. In another embodiment of the presentinvention, s is 1 or 3. In another embodiment of the present invention,s is 1 or 2. In another embodiment of the present invention, s is 2 or3. In another embodiment of the present invention, s is 0. In anotherembodiment of the present invention, s is 1. In another embodiment ofthe present invention, s is 2. In another embodiment of the presentinvention, s is 3.

In another embodiment of the present invention, t=0, 1, 2 or 3. Inanother embodiment of the present invention, t is 0, 1 or 2. In anotherembodiment of the present invention, t is 0, 1 or 3. In anotherembodiment of the present invention, t is 0, 2 or 3. In anotherembodiment of the present invention, t is 0 or 2. In another embodimentof the present invention, t is 0 or 1. In another embodiment of thepresent invention, t is 0 or 3. In another embodiment of the presentinvention, t is 1, 2 or 3. In another embodiment of the presentinvention, t is 1 or 3. In another embodiment of the present invention,t is 1 or 2. In another embodiment of the present invention, t is 2 or3. In another embodiment of the present invention, t is 0. In anotherembodiment of the present invention, t is 1. In another embodiment ofthe present invention, t is 2. In another embodiment of the presentinvention, t is 3.

In another embodiment of the present invention, u=0, 1, 2 or 3. Inanother embodiment of the present invention, u is 0, 1 or 2. In anotherembodiment of the present invention, u is 0, 1 or 3. In anotherembodiment of the present invention, u is 0, 2 or 3. In anotherembodiment of the present invention, u is 0 or 2. In another embodimentof the present invention, u is 0 or 1. In another embodiment of thepresent invention, u is 0 or 3. In another embodiment of the presentinvention, u is 1, 2 or 3. In another embodiment of the presentinvention, u is 1 or 3. In another embodiment of the present invention,u is 1 or 2. In another embodiment of the present invention, u is 2 or3. In another embodiment of the present invention, u is 0. In anotherembodiment of the present invention, u is 1. In another embodiment ofthe present invention, u is 2. In another embodiment of the presentinvention, u is 3.

In another embodiment of the present invention, v=0, 1, 2 or 3. Inanother embodiment of the present invention, v is 0, 1 or 2. In anotherembodiment of the present invention, v is 0, 1 or 3. In anotherembodiment of the present invention, v is 0, 2 or 3. In anotherembodiment of the present invention, v is 0 or 2. In another embodimentof the present invention, v is 0 or 1. In another embodiment of thepresent invention, v is 0 or 3. In another embodiment of the presentinvention, v is 1, 2 or 3. In another embodiment of the presentinvention, v is 1 or 3. In another embodiment of the present invention,v is 1 or 2. In another embodiment of the present invention, v is 2 or3. In another embodiment of the present invention, v is 0. In anotherembodiment of the present invention, v is 1. In another embodiment ofthe present invention, v is 2. In another embodiment of the presentinvention, v is 3.

In another embodiment of the present invention, w=0, 1, 2 or 3. Inanother embodiment of the present invention, w is 0, 1 or 2. In anotherembodiment of the present invention, w is 0, 1 or 3. In anotherembodiment of the present invention, w is 0, 2 or 3. In anotherembodiment of the present invention, w is 0 or 2. In another embodimentof the present invention, w is 0 or 1. In another embodiment of thepresent invention, w is 0 or 3. In another embodiment of the presentinvention, w is 1, 2 or 3. In another embodiment of the presentinvention, w is 1 or 3. In another embodiment of the present invention,w is 1 or 2. In another embodiment of the present invention, w is 2 or3. In another embodiment of the present invention, w is 0. In anotherembodiment of the present invention, w is 1. In another embodiment ofthe present invention, w is 2. In another embodiment of the presentinvention, w is 3.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

wherein B is selected from: phenyl and pyridyl; or a pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

wherein B is selected from: phenyl and pyridyl; or a pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

wherein B is selected from: phenyl and pyridyl; or a pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Id:

wherein B is selected from: phenyl and pyridyl; or a pharmaceuticallyacceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula If:

or a pharmaceutically acceptable salt thereof.

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ig:

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I, includes the compounds ofstructural formulas Ia, Ib, Ic, Id, Ie, If and Ig, and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is phenyl;B is selected from the group consisting of:

(1) phenyl, and

(2) pyridyl;

R¹ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each —C₁₋₆alkyl is unsubstituted or substituted with one to foursubstituents selected from halogen;R² is halogen;R³ when present is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen;R⁴ is selected from:

(1) —OC₁₋₆alkyl, and

(2) —C₁₋₆alkyl,

wherein —C₁₋₆alkyl is unsubstituted or substituted with one, two, threeor four substituents selected from R⁵;R⁵ is selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl,

(3) —OH,

(4) —SO₂C₁₋₆alkyl, and

Y is O; Z is —OH;

m is 0, 1, 2 or 3;n is 1 or 2;p is 1; andq is 1.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is phenyl;B is phenyl;R¹ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each —C₁₋₆alkyl is unsubstituted or substituted with one to foursubstituents selected from halogen;R² is halogen;R³ when present is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen;R⁴ is selected from:

(1) —OC₁₋₆alkyl, and

(2) —C₁₋₆alkyl,

wherein —C₁₋₆alkyl is unsubstituted or substituted with one, two, threeor four substituents selected from R⁵;R⁵ is selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl,

(3) —OH,

(4) —SO₂C₁₋₆alkyl, and

Y is O; Z is —OH;

m is 0, 1, 2 or 3;n is 1 or 2;p is 1; andq is 1.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is phenyl;

B is pyridyl;

R¹ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each —C₁₋₆alkyl is unsubstituted or substituted with one to foursubstituents selected from halogen;R² is halogen;R³ when present is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl;

R⁴ is —OC₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted or substitutedwith one, two, three or four substituents selected from R⁵;R⁵ is selected from the group consisting of:

(1) halogen,

(2) —C₁₋₆alkyl,

(3) —OH,

(4) —SO₂C₁₋₆alkyl, and

Y is O; Z is OH;

m is 0, 1, 2 or 3;n is 1 or 2;p is 1; andq is 1.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is phenyl;B is phenyl or pyridyl;R¹ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein —C₁₋₆alkyl is unsubstituted or substituted with one to foursubstituents selected from halogen;R² is halogen;R³ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen;R⁴ is OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one substituentselected from R⁵;R⁵ is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —(CH₂)_(s)OH,

(3) —(CH₂)_(s)SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen; andZ is selected from:

(1) hydrogen,

(2) —C₁₋₆alkyl,

(3) —(CH₂)_(s)—O—C₁₋₆alkyl, and

(4) —(CH₂)_(s)—OH,

wherein each CH₂, and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen;or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is:

B is phenyl or pyridyl;R¹ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein —C₁₋₆alkyl is unsubstituted or substituted with one to foursubstituents selected from halogen;R² is halogen;R³ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen;R⁴ is OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one substituentselected from R⁵;R⁵ is selected from the group consisting of:

(1) —C₁₋₆alkyl,

(2) —OH,

(3) —SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen;Z is —(CH₂)_(s)—OH;or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

A is

B is phenyl;R¹ is —C₁₋₆alkyl, wherein each —C₁₋₆alkyl is substituted with one, twoor three substituents selected from halogen;

R² is F;

R³ is selected from the group consisting of:

(1) halogen, and

(2) —C₁₋₆alkyl,

wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen;R⁴ is OC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one substituentselected from R⁵;R⁵ is selected from the group consisting of:

(1) —C₁₋₆alkyl, and

(2) —(CH₂)_(s)OH,

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen;or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as agonists of G-protein-coupled receptor 40(GPR40) are the following compounds:

and pharmaceutically acceptable salts thereof.

In one embodiment of the present invention, the compounds of formula Ihave the absolute stereochemistry at the two stereogenic carbon centersas indicated in the compound of structural formula Ie:

and pharmaceutically acceptable salts thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating GPR40 mediateddiseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein. Where a stereochemical center isnot defined, the structure represents a mixture of stereoisomers at thatcenter. For such compounds, the individual stereoisomers, includingenantiomers, diastereoisomers, and mixtures of these are also compoundsof the invention.

DEFINITIONS

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Cycloalkyl” means a saturated monocyclic, bicyclic or bridgedcarbocyclic ring, having a specified number of carbon atoms. The termmay also be used to describe a carbocyclic ring fused to an aryl group.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and the like. In one embodiment of the presentinvention, cycloalkyl is selected from: cyclopropane, cyclobutane andcyclohexane. In another embodiment of the present invention, cycloalkylis cyclopropane.

“Halogen” includes fluorine, chlorine, bromine and iodine. In anotherembodiment of the present invention, halogen includes fluorine, chlorineand iodine. In another embodiment of the present invention, halogenincludes fluorine and chlorine. In another embodiment of the presentinvention, halogen is chlorine. In another embodiment of the presentinvention, halogen is fluorine.

“Me” represents methyl.

When any variable (e.g., R¹, Ra, etc.) occurs more than one time in anyconstituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e., R¹, R²,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

The term “% enantiomeric excess” (abbreviated “ee”) shall mean the %major enantiomer less the % minor enantiomer. Thus, a 70% enantiomericexcess corresponds to formation of 85% of one enantiomer and 15% of theother. The term “enantiomeric excess” is synonymous with the term“optical purity.”

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to encompass all such isomeric forms of the compoundsof Formula I.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

Salts:

It will be understood that, as used herein, references to the compoundsof the present invention are meant to also include the pharmaceuticallyacceptable salts, and also salts that are not pharmaceuticallyacceptable when they are used as precursors to the free compounds ortheir pharmaceutically acceptable salts or in other syntheticmanipulations.

The compounds of the present invention may be administered in the formof a pharmaceutically acceptable salt. The term “pharmaceuticallyacceptable salt” refers to salts prepared from pharmaceuticallyacceptable non-toxic bases or acids including inorganic or organic basesand inorganic or organic acids. Salts of basic compounds encompassedwithin the term “pharmaceutically acceptable salt” refer to non-toxicsalts of the compounds of this invention which are generally prepared byreacting the free base with a suitable organic or inorganic acid.Representative salts of basic compounds of the present inventioninclude, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof include, butare not limited to, salts derived from inorganic bases includingaluminum, ammonium, calcium, copper, ferric, ferrous, lithium,magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassium,and sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary, and tertiaryamines, cyclic amines, and basic ion-exchange resins, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds of the present invention, pharmaceuticallyacceptable esters of carboxylic acid derivatives, such as methyl, ethyl,or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

Solvates, and in particular, the hydrates of the compounds of thepresent invention are included in the present invention as well.

Utilities

The compounds of the present invention are potent agonists of the GPR40receptor. The compounds, and pharmaceutically acceptable salts thereof,may be efficacious in the treatment of diseases that are modulated byGPR40 ligands, which are generally agonists. Many of these diseases aresummarized below.

One or more of these diseases may be treated by the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, to a patient in need oftreatment. Also, the compounds of the present invention may be used forthe manufacture of a medicament which may be useful for treating one ormore of these diseases: (1) non-insulin dependent diabetes mellitus(Type 2 diabetes); (2) hyperglycemia; (3) insulin resistance; (4)Metabolic Syndrome; (5) obesity; (6) hypercholesterolemia; (7)hypertriglyceridemia (elevated levels oftriglyceride-rich-lipoproteins); (8) mixed or diabetic dyslipidemia; (9)low HDL cholesterol; (10) high LDL cholesterol; (11)hyperapo-B-liproteinemia; and (12) atherosclerosis.

Preferred uses of the compounds may be for the treatment of one or moreof the following diseases by administering a therapeutically effectiveamount to a patient in need of treatment. The compounds may be used formanufacturing a medicament for the treatment of one or more of thesediseases: (1) Type 2 diabetes, and specifically hyperglycemia associatedwith Type 2 diabetes; (2) Metabolic Syndrome; (3) obesity; and (4)hypercholesterolemia.

The compounds may be effective in lowering glucose and lipids indiabetic patients and in non-diabetic patients who have impaired glucosetolerance and/or are in a pre-diabetic condition. The compounds mayameliorate hyperinsulinemia, which often occurs in diabetic orpre-diabetic patients, by modulating the swings in the level of serumglucose that often occurs in these patients. The compounds may also beeffective in treating or reducing insulin resistance. The compounds maybe effective in treating or preventing gestational diabetes.

The compounds may also be effective in treating or preventing lipiddisorders. The compounds may be effective in treating or preventingdiabetes related disorders. The compounds may also be effective intreating or preventing obesity related disorders.

The compounds of this invention may also have utility in improving orrestoring β-cell function, so that they may be useful in treating Type 1diabetes or in delaying or preventing a patient with Type 2 diabetesfrom needing insulin therapy.

The invention also includes pharmaceutically acceptable salts of thecompounds, and pharmaceutical compositions comprising the compounds anda pharmaceutically acceptable carrier. The compounds may be useful intreating insulin resistance, Type 2 diabetes, hypperglycemia, anddyslipidemia that is associated with Type 2 diabetes and insulinresistance. The compounds may also be useful for the treatment ofobesity

A compound of the present invention, or a pharmaceutically acceptablesalt thereof, may be used in the manufacture of a medicament for thetreatment of Type 2 diabetes in a human or other mammalian patient.

A method of treating Type 2 diabetes comprises the administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound, to a patient in need of treatment.Other medical uses of the compounds of the present invention aredescribed herein.

Certain compounds of the present invention of formula Id have theunexpected benefit of lower clearance in standard pharmacokinetic assaysdone in preclinical species, such as dogs and rats, compared to thecorresponding compounds with no R¹ and R² substituents. Due to the lowerclearance, these compounds of the present invention exhibit a longerhalf life (or a longer mean residence time).

Certain compounds of the present invention such as compounds in whichthe A ring is substituted with one R² substituent selected from halogen,and the A ring is also substituted with at least one R¹ substituent, andin which the B-ring is pyridyl substituted with at least one R³substituent have the unexpected benefit of improved potency compared tothe corresponding compounds in which the A ring is unsubstituted (i.e.compounds with no R¹ and R² substituents on the A ring) and in which theB-ring is pyridyl substituted with at least one R³ substituent.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type 2 diabetics are also obese. The compositions of thepresent invention may be useful for treating both Type 1 and Type 2diabetes. The term “diabetes associated with obesity” refers to diabetescaused by obesity or resulting from obesity.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. A pre diabeticsubject is someone suffering from prediabetes. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of ≧140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat a diabeticsubject. One outcome of treatment may be decreasing the glucose level ina subject with elevated glucose levels. Another outcome of treatment maybe decreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensivity. Another outcome of treatmentmay be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to meandisorders that are associated with, caused by, or result from diabetes.Examples of diabetes related disorders include retinal damage, kidneydisease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of an anti-obesity agentin combination with a therapeutically effective amount of ananti-hypertensive agent may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists. Theterm “atherosclerosis related disorders” should be understood to meandisorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (≧140 mmHg/≧90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as less than 120 mmHg systolic and less than 80 mmHg diastolic.A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecompounds and combinations of the present invention to treathypertension in a hypertensive subject. Treatment ofhypertension-related disorder refers to the administration of a compoundor combination of the present invention to treat thehypertension-related disorder. Prevention of hypertension, or ahypertension related disorder, refers to the administration of thecombinations of the present invention to a pre-hypertensive subject toprevent the onset of hypertension or a hypertension related disorder.The hypertension-related disorders herein are associated with, causedby, or result from hypertension. Examples of hypertension-relateddisorders include, but are not limited to: heart disease, heart failure,heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolismincluding various conditions characterized by abnormal concentrations ofone or more lipids (i.e. cholesterol and triglycerides), and/orapolipoproteins (i.e., apolipoproteins A, B, C and E), and/orlipoproteins (i.e., the macromolecular complexes formed by the lipid andthe apolipoprotein that allow lipids to circulate in blood, such as LDL,VLDL and IDL). Hyperlipidemia is associated with abnormally high levelsof lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment ofdyslipidemia refers to the administration of the combinations of thepresent invention to a dyslipidemic subject. Prevention of dyslipidemiarefers to the administration of the combinations of the presentinvention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is asubject with higher than normal lipid levels, that is not yetdyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder relateddisorders” should be understood to mean disorders associated with,caused by, or resulting from dyslipidemia or lipid disorders. Examplesof dylipidemia related disorder and lipid disorder related disordersinclude, but are not limited to: hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high density lipoprotein (HDL) levels, highplasma low density lipoprotein (LDL) levels, atherosclerosis and itssequelae, coronary artery or carotid artery disease, heart attack, andstroke.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². An overweightsubject is a subject at risk of obesity. A “subject at risk of obesity”is an otherwise healthy subject with a BMI of 25 kg/m² to less than 30kg/m² or a subject with at least one co-morbidity with a BMI of 25 kg/m²to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes mellitus, non-insulin dependent diabetesmellitus—type 2, diabetes associated with obesity, impaired glucosetolerance, impaired fasting glucose, insulin resistance syndrome,dyslipidemia, hypertension, hypertension associated with obesity,hyperuricacidemia, gout, coronary artery disease, myocardial infarction,angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fattyliver; cerebral infarction, cerebral thrombosis, transient ischemicattack, orthopedic disorders, arthritis deformans, lumbodynia,emmeniopathy, and infertility. In particular, co-morbidities include:hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,cardiovascular disease, sleep apnea, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer. The compounds of the present inventionare also useful for reducing the risk of secondary outcomes of obesity,such as reducing the risk of left ventricular hypertrophy.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III, or ATP III), National Institutesof Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA,vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined ashaving metabolic syndrome if the person has three or more of thefollowing disorders: abdominal obesity, hypertriglyceridemia, low HDLcholesterol, high blood pressure, and high fasting plasma glucose. Thecriteria for these are defined in ATP-III. Treatment of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with metabolic syndrome. Prevention of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with two of the disorders that define metabolicsyndrome. A subject with two of the disorders that define metabolicsyndrome is a subject that has developed two of the disorders thatdefine metabolic syndrome, but has not yet developed three or more ofthe disorders that define metabolic syndrome.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual, human or other mammalin need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician or veterinarian in charge of the case, butdepends on factors such as the exact disease to be treated, the severityof the disease and other diseases or conditions from which the patientsuffers, the chosen route of administration other drugs and treatmentswhich the patient may concomitantly require, and other factors in thephysician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

In the treatment or prevention of conditions which require agonism ofGPR40 receptor activity, an appropriate dosage level will generally beabout 0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000 mg ofthe active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0,50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,750.0, 800.0, 900.0, and 1000.0 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day,preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata daily dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 mg to about1000 mg, preferably from about 1 mg to about 50 mg. In the case of a 70kg adult human, the total daily dose will generally be from about 7 mgto about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

Additionally, in the treatment or prevention of conditions which requireagonism of GPR40 receptor activity, an appropriate dosage level willgenerally be about 0.01 to 500 mg per kg patient body weight per week,which can be administered in single or multiple doses. Preferably, thedosage level will be about 0.1 to about 250 mg/kg per week; morepreferably about 0.5 to about 100 mg/kg per week. A suitable dosagelevel may be about 0.01 to 250 mg/kg per week, about 0.05 to 100 mg/kgper week, or about 0.1 to 50 mg/kg per week. Within this range thedosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per week. For oraladministration, the compositions are preferably provided in the form oftablets containing 1.0 to 1000 mg of the active ingredient, particularly1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The compounds may also be administered on aregimen of 1 to 4 times per week, preferably once or twice per week.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of thepresent invention are indicated, generally satisfactory results areobtained when the compounds of the present invention are administered ata weekly dosage of from about 0.1 mg to about 100 mg per kilogram ofanimal body weight, preferably given as a single weekly dose or individed doses two to six times a week, or in sustained release form. Formost large mammals, the total weekly dosage is from about 1.0 mg toabout 1000 mg, preferably from about 1 mg to about 50 mg. In the case ofa 70 kg adult human, the total weekly dose will generally be from about7 mg to about 350 mg. This dosage regimen may be adjusted to provide theoptimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of this invention may be used in pharmaceuticalcompositions comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds of this invention may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this invention may also be used inpharmaceutical compositions in which the compound of the presentinvention or a pharmaceutically acceptable salt thereof is the onlyactive ingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Compounds of the present invention may be used in combination with otherdrugs that may also be useful in the treatment or amelioration of thediseases or conditions for which compounds of the present invention areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of the present invention. In the treatment of patients who haveType 2 diabetes, insulin resistance, obesity, metabolic syndrome, andco-morbidities that accompany these diseases, more than one drug iscommonly administered. The compounds of this invention may generally beadministered to a patient who is already taking one or more other drugsfor these conditions. Often the compounds will be administered to apatient who is already being treated with one or more antidiabeticcompound, such as metformin, sulfonylureas, and/or PPARγ agonists, whenthe patient's glycemic levels are not adequately responding totreatment.

When a compound of the present invention is used contemporaneously withone or more other drugs, a pharmaceutical composition in unit dosageform containing such other drugs and the compound of the presentinvention is preferred. However, the combination therapy also includestherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compound of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention.

Examples of other active ingredients that may be administered separatelyor in the same pharmaceutical composition in combination with a compoundof the formulas described herein include, but are not limited to:

(1) other dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin,alogliptin, linagliptin, vildagliptin, saxagliptin, teneligliptin,omarigliptin);

(2) insulin sensitizers, including (i) PPARγ agonists, such as theglitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARaky dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARa agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARγ modulators (SPPARγM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814);

(3) insulin or insulin analogs (e.g., insulin detemir, insulinglulisine, insulin degludec, insulin glargine, insulin lispro, SBS1000and oral and inhalable formulations of insulin and insulin analogs);

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs (e.g., pramlintide);

(6) sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide);

(7) α-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists (e.g., NOXG15, LY2409021);

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, andmimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide,albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide,GSK2374697, ADX72231, RG7685, NN9924, ZYOG1, CJC-1131, and BIM-51077,including intranasal, transdermal, and once-weekly formulationsthereof), and oxyntomodulin and oxyntomodulin analogs and derivatives;

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (e.g., simvastatin, lovastatin, pravastatin, crivastatin,fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bileacid sequestering agents (e.g., colestilan, colestimide, colesevalamhydrochloride, colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) inhibitors of cholesterolabsorption, (e.g., ezetimibe), and (iv) acyl CoA: cholesterolacyltransferase inhibitors, (e.g., avasimibe);

(11) HDL-raising drugs, (e.g., niacin and nicotinic acid receptoragonists, and extended-release versions thereof;

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such asaspirin, non-steroidal anti-inflammatory drugs or NSAIDs,glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (e.g., lisinopril,enalapril, ramipril, captopril, quinapril, and tandolapril), A-IIreceptor blockers (e.g., losartan, candesartan, irbesartan, olmesartanmedoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors(e.g., aliskiren), beta blockers, and calcium channel blockers;

(15) glucokinase activators (GKAs) (e.g., AZD6370);

(16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, (e.g., suchas those disclosed in U.S. Pat. No. 6,730,690, and LY-2523199);

(17) CETP inhibitors (e.g., anacetrapib, evacetrapib and torcetrapib);

(18) inhibitors of fructose 1,6-bisphosphatase, (e.g., such as thosedisclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782;and 6,489,476);

(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);

(20) AMP-activated Protein Kinase (AMPK) activators, such as MB1055, ETC1002;

(21) other agonists of the G-protein-coupled receptors: (i) GPR-109,(ii) GPR-119 (e.g., MBX2982, APD597, GSK1292263, HM47000, and PSN821),and (iii) GPR-40 (e.g., TAK875, MR 1704, TUG 469, TUG499, ASP 4178);

(22) SSTR3 antagonists (e.g., such as those disclosed in WO2009/001836);

(23) neuromedin U receptor agonists (e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS));

(24) SCD inhibitors;

(25) GPR-105 antagonists (e.g., such as those disclosed in WO2009/000087);

(26) SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin,dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin,TS-071, tofogliflozin, ipragliflozin, and LX-4211);

(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and2 (DGAT-1 and DGAT-2);

(28) inhibitors of fatty acid synthase;

(29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1and 2 (MGAT-1 and MGAT-2);

(30) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR);

(31) ileal bile acid transporter inhibitors;

(32) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

(33) PPAR agonists;

(34) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(35) IL-lb antibodies, (e.g., XOMA052 and canakinumab);

(36) bromocriptine mesylate and rapid-release formulations thereof;

(37) GPR 120 agonists (such as KDT501.

Other suitable active ingredients/pharmaceutical agents that may beadministered in combination with a compound of the present invention,and either administered separately or in the same pharmaceuticalcomposition, include, but are not limited to:

(a) anti-diabetic agents such as (1) PPARγ agonists such as glitazones(e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555);pioglitazone (ACTOS); rosiglitazone (AVANDIA); troglitazone;rivoglitazone, BRL49653; CLX-0921; 5-BTZD, GW-0207, LG-100641, R483, andLY-300512, and the like and compounds disclosed in WO97/10813, 97/27857,97/28115, 97/28137, 97/27847, 03/000685, and 03/027112 and SPPARMS(selective PPAR gamma modulators) such as T131 (Amgen), FK614(Fujisawa), netoglitazone, and metaglidasen; (2) biguanides such asbuformin; metformin; and phenformin, and the like; (3) protein tyrosinephosphatase-1B (PTP-1B) inhibitors such as ISIS 113715, A-401674,A-364504, IDD-3, IDD 2846, KP-40046, KR61639, MC52445, MC52453, C7,OC-060062, OC-86839, OC29796, TTP-277BC1, and those agents disclosed inWO 04/041799, 04/050646, 02/26707, 02/26743, 04/092146, 03/048140,04/089918, 03/002569, 04/065387, 04/127570, and US 2004/167183; (4)sulfonylureas such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide, andthe like; (5) meglitinides such as repaglinide, metiglinide (GLUFAST)and nateglinide, and the like; (6) alpha glucoside hydrolase inhibitorssuch as acarbose; adiposine; camiglibose; emiglitate; miglitol;voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945;and MOR 14, and the like; (7) alpha-amylase inhibitors such astendamistat, trestatin, and A1-3688, and the like; (8) insulinsecreatagogues such as linogliride nateglinide, mitiglinide (GLUFAST),ID1101 A-4166, and the like; (9) fatty acid oxidation inhibitors, suchas clomoxir, and etomoxir, and the like; (10) A2 antagonists, such asmidaglizole; isaglidole; deriglidole; idazoxan; earoxan; and fluparoxan,and the like; (11) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (17-36),GLP-1 (73-7) (insulintropin); GLP-1 (7-36)-NH₂) exenatide/Exendin-4,Exenatide LAR, Linaglutide, AVE0010, CJC 1131, BIM51077, CS 872, TH0318,BAY-694326, GP010, ALBUGON (GLP-1 fused to albumin), HGX-007 (Epacagonist), S-23521, and compounds disclosed in WO 04/022004, WO 04/37859,and the like; (12) non-thiazolidinediones such as JT-501, andfarglitazar (GW-2570/GI-262579), and the like; (13) PPARα/γ dualagonists such as AVE 0847, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297,L-796449, LBM 642, LR-90, LY510919, MK-0767, ONO 5129, SB 219994,TAK-559, TAK-654, 677954 (GlaxoSmithkline), E-3030 (Eisai), LY510929(Lilly), AK109 (Asahi), DRF2655 (Dr. Reddy), DRF8351 (Dr. Reddy), MC3002(Maxocore), TY51501 (ToaEiyo), farglitazar, naveglitazar, muraglitazar,peliglitazar, tesaglitazar (GALIDA), reglitazar (JT-501), chiglitazar,and those disclosed in WO 99/16758, WO 99/19313, WO 99/20614, WO99/38850, WO 00/23415, WO 00/23417, WO 00/23445, WO 00/50414, WO01/00579, WO 01/79150, WO 02/062799, WO 03/033481, WO 03/033450, WO03/033453; and (14), insulin, insulin mimetics and other insulinsensitizing drugs; (15) VPAC2 receptor agonists; (16) GLK modulators,such as PSN105, RO 281675, RO 274375 and those disclosed in WO03/015774, WO 03/000262, WO 03/055482, WO 04/046139, WO 04/045614, WO04/063179, WO 04/063194, WO 04/050645, and the like; (17) retinoidmodulators such as those disclosed in WO 03/000249; (18) GSK 3beta/GSK 3inhibitors such as4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazol-5-yl]pyridine,CT21022, CT20026, CT-98023, SB-216763, SB410111, SB-675236, CP-70949,XD4241 and those compounds disclosed in WO 03/037869, 03/03877,03/037891, 03/024447, 05/000192, 05/019218 and the like; (19) glycogenphosphorylase (HGLPa) inhibitors, such as AVE 5688, PSN 357, GPi-879,those disclosed in WO 03/037864, WO 03/091213, WO 04/092158, WO05/013975, WO 05/013981, US 2004/0220229, and JP 2004-196702, and thelike; (20) ATP consumption promotors such as those disclosed in WO03/007990; (21) fixed combinations of PPAR γ agonists and metformin suchas AVANDAMET; (22) PPAR pan agonists such as GSK 677954; (23) GPR40(G-protein coupled receptor 40) also called SNORF 55 such as BG 700, andthose disclosed in WO 04/041266, 04/022551, 03/099793; (24) GPR119(G-protein coupled receptor 119, also called RUP3; SNORF 25) such asRUP3, HGPRBMY26, PFI 007, SNORF 25; (25) adenosine receptor 2Bantagonists such as ATL-618, AT1-802, E3080, and the like; (26)carnitine palmitoyl transferase inhibitors such as ST 1327, and ST 1326,and the like; (27) Fructose 1,6-bisphospohatase inhibitors such asCS-917, MB7803, and the like; (28) glucagon antagonists such as AT77077,BAY 694326, GW 4123X, NN2501, and those disclosed in WO 03/064404, WO05/00781, US 2004/0209928, US 2004/029943, and the like; (30)glucose-6-phosphase inhibitors; (31) phosphoenolpyruvate carboxykinase(PEPCK) inhibitors; (32) pyruvate dehydrogenase kinase (PDK) activators;(33) RXR agonists such as MC1036, CS00018, JNJ 10166806, and thosedisclosed in WO 04/089916, U.S. Pat. No. 6,759,546, and the like; (34)SGLT inhibitors such as AVE 2268, KGT 1251, T1095/RWJ 394718; (35)BLX-1002; (36) alpha glucosidase inhibitors; (37) glucagon receptoragonists; (38) glucokinase activators; 39) GIP-1; 40) insulinsecretagogues; 41) GPR-40 agonists, such as TAK-875,5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-1H-indene-1-yl]oxy]phenyl]isothiazole-3-ol1-oxide, 5-(4-((3-(2,6-dimethyl-4-(3(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)-phenyl)iso,5-(4-((3-(2-methyl-6-(3-hydroxypropoxy)pyridine-3-yl)-2-methylphenyl)methoxy)-phenyl)isothiazole-3-ol1-oxide, and5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]-phenyl]methoxy]phenyl]isothiazole-3-ol1-oxide), and those disclosed in WO 11/078371.

(b) anti-dyslipidemic agents such as (1) bile acid sequestrants such as,cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivativesof a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and thelike; (2) HMG-CoA reductase inhibitors such as atorvastatin,itavastatin, pitavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, simvastatin, rosuvastatin (ZD-4522), and other statins,particularly simvastatin, atorvastatin or rosuvastatin; (3) HMG-CoAsynthase inhibitors; (4) cholesterol absorption inhibitors such as FMVP4(Forbes Medi-Tech), KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (ForbesMedi-Tech), FM-VP-24 (Forbes Medi-Tech), stanol esters, beta-sitosterol,sterol glycosides such as tiqueside; and azetidinones such as ezetimibe,and those disclosed in WO 04/005247 and the like; (5) acyl coenzymeA-cholesterol acyl transferase (ACAT) inhibitors such as avasimibe,eflucimibe, pactimibe (KY505), SMP 797 (Sumitomo), SM32504 (Sumitomo),and those disclosed in WO 03/091216, and the like; (6) CETP inhibitorssuch as anacetrapib, JTT 705 (Japan Tobacco), torcetrapib, CP 532,632,BAY63-2149 (Bayer), SC 591, SC 795, and the like; (7) squalenesynthetase inhibitors; (8) anti-oxidants such as probucol, and the like;(9) PPARa agonists such as beclofibrate, bezafibrate, ciprofibrate,clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW7647, BM 170744 (Kowa), LY518674 (Lilly), GW590735 (GlaxoSmithkline),KRP-101 (Kyorin), DRF10945 (Dr. Reddy), NS-220/R1593 (NipponShinyaku/Roche, ST1929 (Sigma Tau) MC3001/MC3004 (MaxoCorePharmaceuticals, gemcabene calcium, other fibric acid derivatives, suchas Atromid®, Lopid® and Tricor®, and those disclosed in U.S. Pat. No.6,548,538, and the like; (10) FXR receptor modulators such as GW 4064(GlaxoSmithkline), SR 103912, QRX401, LN-6691 (Lion Bioscience), andthose disclosed in WO 02/064125, WO 04/045511, and the like; (11) LXRreceptor modulators such as GW 3965 (GlaxoSmithkline), T9013137, andXTC0179628 (X-Ceptor Therapeutics/Sanyo), and those disclosed in WO03/031408, WO 03/063796, WO 04/072041, and the like; (12) lipoproteinsynthesis inhibitors such as niacin; (13) renin angiotensin systeminhibitors; (14) PPAR δ partial agonists, such as those disclosed in WO03/024395; (15) bile acid reabsorption inhibitors, such as BARI 1453,SC435, PHA384640, S8921, AZD7706, and the like; and bile acidsequesterants such as colesevelam (WELCHOL/CHOLESTAGEL), colestipol,cholestyramine, and dialkylaminoalkyl derivatives of a cross-linkeddextran, (16) PPARδ agonists such as GW 501516 (Ligand, GSK), GW 590735,GW-0742 (GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly),NNC610050 (Novo Nordisk) and those disclosed in WO97/28149, WO 01/79197,WO 02/14291, WO 02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO03/033493, WO 03/035603, WO 03/072100, WO 03/097607, WO 04/005253, WO04/007439, and JP10237049, and the like; (17) triglyceride synthesisinhibitors; (18) microsomal triglyceride transport (MTTP) inhibitors,such as implitapide, LAB687, JTT130 (Japan Tobacco), CP346086, and thosedisclosed in WO 03/072532, and the like; (19) transcription modulators;(20) squalene epoxidase inhibitors; (21) low density lipoprotein (LDL)receptor inducers; (22) platelet aggregation inhibitors; (23) 5-LO orFLAP inhibitors; and (24) niacin receptor agonists including HM74Areceptor agonists; (25) PPAR modulators such as those disclosed in WO01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/016265, WO03/033453; (26) niacin-bound chromium, as disclosed in WO 03/039535;(27) substituted acid derivatives disclosed in WO 03/040114; (28)infused HDL such as LUV/ETC-588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer),ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), synthetic trimericApoA1, Bioral Apo A1 targeted to foam cells, and the like; (29) IBATinhibitors such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis, PHA384640E(Pfizer), S8921 (Shionogi) AZD7806 (AstrZeneca), AK105 (Asah Kasei), andthe like; (30) Lp-PLA2 inhibitors such as SB480848 (GlaxoSmithkline),659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), and the like; (31)other agents which affect lipic composition including ETC1001/ESP31015(Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin),AZD4619 (AstrZeneca); and

(c) anti-hypertensive agents such as (1) diuretics, such as thiazides,including chlorthalidone, chlorthiazide, dichlorophenamide,hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics,such as bumetanide, ethacrynic acid, furosemide, and torsemide;potassium sparing agents, such as amiloride, and triamterene; andaldosterone antagonists, such as spironolactone, epirenone, and thelike; (2) beta-adrenergic blockers such as acebutolol, atenolol,betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol,celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol,penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, andtimolol, and the like; (3) calcium channel blockers such as amlodipine,aranidipine, azelnidipine, barnidipine, benidipine, bepridil,cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, and verapamil, and the like; (4)angiotensin converting enzyme (ACE) inhibitors such as benazepril;captopril; cilazapril; delapril; enalapril; fosinopril; imidapril;losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril;perindropril; quanipril; spirapril; tenocapril; trandolapril, andzofenopril, and the like; (5) neutral endopeptidase inhibitors such asomapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat, AVE7688,ER4030, and the like; (6) endothelin antagonists such as tezosentan,A308165, and YM62899, and the like; (7) vasodilators such ashydralazine, clonidine, minoxidil, and nicotinyl alcohol, nicotinic acidor salt thereof, and the like; (8) angiotensin II receptor antagonistssuch as candesartan, eprosartan, irbesartan, losartan, pratosartan,tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270,and the like; (9) a/13 adrenergic blockers as nipradilol, arotinolol andamosulalol, and the like; (10) alpha 1 blockers, such as terazosin,urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil,indoramin, WHIP 164, and XEN010, and the like; (11) alpha 2 agonistssuch as lofexidine, tiamenidine, moxonidine, rilmenidine and guanobenz,and the like; (12) aldosterone inhibitors, and the like; (13)angiopoietin-2-binding agents such as those disclosed in WO 03/030833;and

(d) anti-obesity agents, such as (1) 5HT (serotonin) transporterinhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, and imipramine, and those disclosed in WO 03/00663, as wellas serotonin/noradrenaline re uptake inhibitors such as sibutramine(MERIDIA/REDUCTIL) and dopamine uptake inhibitor/Norepenephrine uptakeinhibitors such as radafaxine hydrochloride, 353162 (GlaxoSmithkline),and the like; (2) NE (norepinephrine) transporter inhibitors, such as GW320659, despiramine, talsupram, and nomifensine; (3) CB1 (cannabinoid-1receptor) antagonist/inverse agonists, such as taranabant, rimonabant(ACCOMPLIA Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), AVE1625(Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326(Solvay), CP945598 (Pfizer), E-6776 (Esteve), 01691 (Organix), ORG14481(Organon), VER24343 (Vernalis), NESS0327 (Univ of Sassari/Univ ofCagliari), and those disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837,5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941, 6,028,084, and6,509367; and WO 96/33159, WO97/29079, WO98/31227, WO 98/33765,WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967,WO00/10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO03/007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, WO04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO05/000301, WO 05/016286, WO 05/066126 and EP-658546 and the like; (4)ghrelin agonists/antagonists, such as BVT81-97 (BioVitrum), RC1291(Rejuvenon), SRD-04677 (Sumitomo), unacylated ghrelin(TheraTechnologies), and those disclosed in WO 01/87335, WO 02/08250, WO05/012331, and the like; (5) H3 (histamine H3) antagonist/inverseagonists, such as thioperamide, 3-(1H-imidazol-4-yl)propylN-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan,GT2394 (Gliatech), and A331440, and those disclosed in WO 02/15905; andO-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm(Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)) and histamine H3 receptor modulators such as those disclosed inWO 03/024928 and WO 03/024929; (6) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda), T71(Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464(GlaxoSmithkline), A224940 (Abbott), A798 (Abbott), ATC0175/AR224349(Arena Pharmaceuticals), GW803430 (GlaxoSmithkine), NBI-1A (NeurocrineBiosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847(Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama MedicalSchool/University of California Irvine), and those disclosed WO01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO04/087680; and Japanese Patent Application Nos. JP 13226269, JP 1437059,JP2004315511, and the like; (7) MCH2R (melanin concentrating hormone 2R)agonist/antagonists; (8) NPY1 (neuropeptide Y Y1) antagonists, such asBMS205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, andGI-264879A; and those disclosed in U.S. Pat. No. 6,001,836; and WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5) antagonists,such as 152,804, S2367 (Shionogi), E-6999 (Esteve), GW-569180A,GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X; FR 235,208;FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, C-75(Fasgen) LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, S2367(Shionogi), JCF-104, and H409/22; and those compounds disclosed in U.S.Pat. Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375,6,329,395, 6,335,345, 6,337,332, 6,329,395, and 6,340,683; andEP-01010691, EP-01044970, and FR252384; and PCT Publication Nos. WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO02/094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO05/014592, WO 05/01493; and Norman et al., J. Med. Chem. 43:4288-4312(2000); (10) leptin, such as recombinant human leptin (PEG-OB, HoffmanLa Roche) and recombinant methionyl human leptin (Amgen); (11) leptinderivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524;5,552,523; 5,552,522; 5,521,283; and WO 96/23513; WO 96/23514; WO96/23515; WO 96/23516; WO 96/23517; WO 96/23518; WO 96/23519; and WO96/23520; (12) opioid antagonists, such as nalmefene (Revex®),3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed in WO00/21509; (13) orexin antagonists, such as SB-334867-A(GlaxoSmithkline); and those disclosed in WO 01/96302, 01/68609,02/44172, 02/51232, 02/51838, 02/089800, 02/090355, 03/023561,03/032991, 03/037847, 04/004733, 04/026866, 04/041791, 04/085403, andthe like; (14) BRS3 (bombesin receptor subtype 3) agonists; (15) CCK-A(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180,A-71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide,and those disclosed in U.S. Pat. No. 5,739,106; (16) CNTF (ciliaryneurotrophic factors), such as GI-181771 (Glaxo-SmithKline); SR146131(Sanofi Synthelabo); butabindide; and PD170,292, PD 149164 (Pfizer);(17) CNTF derivatives, such as axokine (Regeneron); and those disclosedin WO 94/09134, WO 98/22128, and WO 99/43813; (18) GHS (growth hormonesecretagogue receptor) agonists, such as NN703, hexarelin, MK-0677,SM-130686, CP-424,391, L-692,429 and L-163,255, and those disclosed inU.S. Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and2002/022637; and WO 01/56592, and WO 02/32888; (19) 5HT2c (serotoninreceptor 2c) agonists, such as APD3546/AR10A (Arena Pharmaceuticals),ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK),DPCA37215 (BMS), IK264; LY448100 (Lilly), PNU 22394; WAY 470 (Wyeth),WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche)YM 348; and those disclosed in U.S. Pat. No. 3,914,250; and PCTPublications 01/66548, 02/36596, 02/48124, 02/10169, 02/44152; 02/51844,02/40456, 02/40457, 03/057698, 05/000849, and the like; (20) Mc3r(melanocortin 3 receptor) agonists; (21) Mc4r (melanocortin 4 receptor)agonists, such as CHIR86036 (Chiron), CHIR915 (Chiron); ME-10142(Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (NeurocrineBiosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech) and thosedisclosed in PCT Publications WO 99/64002, 00/74679, 01/991752,01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842,02/059095, 02/059107, 02/059108, 02/059117, 02/062766, 02/069095,02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388,02/067869, 02/081430, 03/06604, 03/007949, 03/009847, 03/009850,03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610,04/075823, 04/083208, 04/089951, 05/000339, and EP 1460069, and US2005049269, and JP2005042839, and the like; (22) monoamine reuptakeinhibitors, such as sibutratmine (Meridia®/Reductil®) and salts thereof,and those compounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570,and 5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO01/27068, and WO 01/62341; (23) serotonin reuptake inhibitors, such asdexfenfluramine, fluoxetine, and those in U.S. Pat. No. 6,365,633, andWO 01/27060, and WO 01/162341; (24) GLP-1 (glucagon-like peptide 1)agonists; (25) Topiramate (Topimax®); (26) phytopharm compound 57 (CP644,673); (27) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (28) β3 (betaadrenergic receptor 3) agonists, such as rafebergron/AD9677/TAK677(Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (GlenmarkPharmaceuticals) GW 427353 (solabegron hydrochloride), Trecadrine,Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), KT07924(Kissei), SR 59119A, and those disclosed in U.S. Pat. No. 5,705,515,U.S. Pat. No. 5,451,677; and WO94/18161, WO95/29159, WO97/46556,WO98/04526 WO98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO04/108674, and the like; (29) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (30) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(31) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75;(32) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast, as well as those described in WO 03/037432, WO03/037899; (33) thyroid hormone 13 agonists, such as KB-2611(KaroBioBMS), and those disclosed in WO 02/15845; and Japanese PatentApplication No. JP 2000256190; (34) UCP-1 (uncoupling protein 1), 2, or3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123;(35) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa,M. et al., Obesity Research, 9:202-9 (2001); (36) glucocorticoidreceptor antagonists, such as CP472555 (Pfizer), KB 3305, and thosedisclosed in WO 04/000869, WO 04/075864, and the like; (37) 11β HSD-1(11-beta hydroxy steroid dehydrogenase type 1) inhibitors, such as BVT3498 (AMG 331), BVT 2733,3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole,3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene,and those compounds disclosed in WO 01/90091, 01/90090, 01/90092,02/072084, 04/011410, 04/033427, 04/041264, 04/027047, 04/056744,04/065351, 04/089415, 04/037251, and the like; (38) SCD-1 (stearoyl-CoAdesaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DPP-4)inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,sitagliptin (Januvia), saxagliptin, alogliptin, NVP-DPP728, LAF237(vildagliptin), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364,VIP 0177, SDZ 274-444, GSK 823093, E 3024, SYR 322, TS021, SSR 162369,GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149, PT-630, SK-0403;and the compounds disclosed in WO 02/083128, WO 02/062764, WO 02/14271,WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/005766, WO03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/0214870, WO04/041273, WO 04/041820, WO 04/050658, WO 04/046106, WO 04/067509, WO04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO05/023762, US 2005/043292, and EP 1 258 476; (40) lipase inhibitors,such as tetrahydrolipstatin (orlistat/XENICAL), ATL962 (Alizyme/Takeda),GT389255 (Genzyme/Peptimmune) Triton WR1339, RHC80267, lipstatin,teasaponin, and diethylumbelliferyl phosphate, FL-386, WAY-121898,Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, and RHC80267, and those disclosed in WO 01/77094, WO 04/111004, and U.S. Pat.Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644,4,189,438, and 4,242,453, and the like; (41) fatty acid transporterinhibitors; (42) dicarboxylate transporter inhibitors; (43) glucosetransporter inhibitors; and (44) phosphate transporter inhibitors; (45)anorectic bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis),and the compounds disclosed in WO 00/18749, WO 01/32638, WO 01/62746, WO01/62747, and WO 03/015769; (46) peptide YY and PYY agonists such asPYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin),TM30335/TM30338 (7TM Pharma), PYY336 (Emisphere Tehcnologies), pegylatedpeptide YY3-36, those disclosed in WO 03/026591, 04/089279, and thelike; (47) lipid metabolism modulators such as maslinic acid,erythrodiol, ursolic acid uvaol, betulinic acid, betulin, and the likeand compounds disclosed in WO 03/011267; (48) transcription factormodulators such as those disclosed in WO 03/026576; (49) Mc5r(melanocortin 5 receptor) modulators, such as those disclosed in WO97/19952, WO 00/15826, WO 00/15790, US 20030092041, and the like; (50)Brain derived neutotropic factor (BDNF), (51) Mr1r (melanocortin 1receptor modulators such as LK-184 (Proctor & Gamble), and the like;(52) 5HT6 antagonists such as BVT74316 (BioVitrum), BVT5182c(BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885(GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche), andthe like; (53) fatty acid transport protein 4 (FATP4); (54) acetyl-CoAcarboxylase (ACC) inhibitors such as CP640186, CP610431, CP640188(Pfizer); (55) C-terminal growth hormone fragments such as AOD9604(Monash Univ/Metabolic Pharmaceuticals), and the like; (56)oxyntomodulin; (57) neuropeptide FF receptor antagonists such as thosedisclosed in WO 04/083218, and the like; (58) amylin agonists such asSymlin/pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulonextracts; (60) BVT74713 and other gut lipid appetite suppressants; (61)dopamine agonists such as bupropion (WELLBUTRIN/GlaxoSmithkline); (62)zonisamide (ZONEGRAN/Dainippon/Elan), and the like; and

(e) anorectic agents suitable for use in combination with a compound ofthe present invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof. A particularly suitable classof anorectic agent are the halogenated amphetamine derivatives,including chlorphentermine, cloforex, clortermine, dexfenfluramine,fenfluramine, picilorex and sibutramine; and pharmaceutically acceptablesalts thereof. Particular halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,rosuvastatin, sitagliptin, metformin, sibutramine, orlistat, Qnexa,topiramate, naltrexone, bupriopion, phentermine, and losartan, losartanwith hydrochlorothiazide.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:l′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{1′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof.

Specific MCH1R antagonist compounds of use in combination with acompound of the present invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from Januvia,7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific H3 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905, including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxylphenyl)-4(3H)-quinazolinone,2-methyl-3-(4-‡3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone, and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof.

Specific MC4R agonists of use in combination with a compound of thepresent invention include: 1)(5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile;and pharmaceutically acceptable salts thereof.

Suitable neurokinin-1 (NK-1) receptor antagonists may be favorablyemployed with the AMP-kinase activators of the present invention. NK-1receptor antagonists of use in the present invention are fully describedin the art. Specific neurokinin-1 receptor antagonists of use in thepresent invention include:(±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763; or a pharmaceuticallyacceptable salts thereof.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds with two or more active compounds selected from biguanides,sulfonylureas, HMG-CoA reductase inhibitors, PPARγ agonists, DPP-4inhibitors, anti-obesity compounds, and anti-hypertensive agents.

The present invention also provides a method for the treatment orprevention of a G-protein coupled receptor 40 (GPR40) mediated disease,which method comprises administration to a patient in need of suchtreatment or at risk of developing a GPR40 mediated disease of an amountof a GPR40 agonist and an amount of one or more active ingredients, suchthat together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a GPR40 agonist and one or moreactive ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of a GPR40 agonist and one or more active ingredientsfor the manufacture of a medicament for the treatment or prevention of aGPR40 mediated disease. In a further or alternative aspect of thepresent invention, there is therefore provided a product comprising aGPR40 agonist and one or more active ingredients as a combinedpreparation for simultaneous, separate or sequential use in thetreatment or prevention of a GPR40 mediated disease. Such a combinedpreparation may be, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of diabetes,obesity, hypertension, Metabolic Syndrome, dyslipidemia, cancer,atherosclerosis, and related disorders thereof, a compound of thepresent invention may be used in conjunction with another pharmaceuticalagent effective to treat that disorder.

The present invention also provides a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent effective to threat that disorder, suchthat together they give effective relief.

The present invention also provides a method for the treatment orprevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, such that together they give effective relief.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a DPIVinhibitor the weight ratio of the compound of the Formula I to the DPIVinhibitor will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of theFormula I and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The following Examples are provided to illustrate the invention and arenot to be construed as limiting the invention in any manner. The scopeof the invention is defined by the appended claims.

Methods of Synthesis of the Compounds of the Present Invention:

The following reaction schemes and Examples illustrate methods which maybe employed for the synthesis of the compounds of structural formula Idescribed in this invention. These reaction schemes and Examples areprovided to illustrate the invention and are not to be construed aslimiting the invention in any manner. All substituents are as definedabove unless indicated otherwise. Several strategies based uponsynthetic transformations known in the literature of organic synthesismay be employed for the preparation of the compounds of structuralformula I. The scope of the invention is defined by the appended claims.

The compounds of the present invention can be prepared according to theprocedures of the following Examples, using appropriate materials. Thecompounds illustrated in the examples are not, however, to be construedas forming the only genus that is considered as the invention. TheExamples further illustrate details for the preparation of the compoundsof the present invention. Those skilled in the art will readilyunderstand that known variations of protecting groups, as well as of theconditions and processes of the following preparative procedures, can beused to prepare these compounds. It is also understood that whenever achemical reagent such as a boronic acid or a boronate is notcommercially available, such a chemical reagent can be readily preparedfollowing one of numerous methods described in the literature. Alltemperatures are degrees Celsius unless otherwise noted. Mass spectra(MS) were measured either by electrospray ion-mass spectroscopy (ESMS)or by atmospheric pressure chemical ionization mass spectroscopy (APCI).

LIST OF ABBREVIATIONS

Ac is acetyl; ACN is acetonitrile; AcO is acetoxy; AcOH is acetic acid;AcONa is sodium acetate; Alk is alkyl; APCI is atmospheric pressurechemical ionization; Ag₂CO₃ is silver carbonate; aq or aq. is aqueous;Ar is aryl; br is broad; BrettPhos Precatalyst ischloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]-palladium(II);bu is butyl; ° C. is degrees celsius; CH₂Cl₂ is dichloromethane; CCl₄ iscarbon tetrachloride; conc or conc. is concentrated; d is doublet; DASTis (diethylamino)sulfur trifluoride; DIAD is diisopropylazodicarboxylate; DCM is dichloromethane; DMAP is4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; dppf is 1,1′-bis(diphenyl-phosphino)ferrocene; ESI iselectrospray ionization; EA or EtOAc is ethyl acetate; et is ethyl; EtOHis ethanol; g or gm is gram(s); h or hr or hrs is hour(s); HPLC is highpressure liquid chromatography; kg is kilogram(s); KHMDS is potassiumhexamethyl disilazide; K₂CO₃ is potassium carbonate; KOAc is potassiumacetate; L is liter; LiOH is lithium hydroxide; m is multiplet; mL or mlis milliliter; min or mins is minute(s); mol is mole(s); mmol ismmole(s); mg is milligram(s); M is molar; MCPBA, mCPBA or m-CPBA ismeta-chloro-peroxybenzoic acid; me is methyl; MeOH is methyl alcohol;MgSO₄ is magnesium sulfate; MS is mass spectroscopy; MsCl or Ms-Cl ismethane sulfonyl chloride or mesyl chloride; MTBE is methyl tert-butylether; N is normal; NaOH is sodium hydroxide; Na₂SO₄ is sodium sulfate;NBS is N-bromo succinamide; NIS is N-iodo succinamide; NMP is1-methyl-2-pyrrolidinone; NMR is nuclear magnetic resonancespectroscopy; PE is petroleum ether; Pd(dppf)Cl₂ is[1,1′-bis(diphenyl-phosphino)ferrocene]-dichloro-palladium (II);Pd(dtbpf)Cl₂ is[1,1′-bis(di-tert-butylphosphino)-ferrocene]dichloro-palladium (II); PMBis para-methoxybenzyl; PMBC1 is para-methoxybenzyl chloride; Pd(PPh₃)₄is tetrakis triphenyl phosphine palladium; prep. TLC or prep-TLC, orpreparative TCL is preparative thin layer chromatography; rt or rt. orr.t. or RT is room temperature; sat. is saturated; s is singlet; t istriplet; TEA is triethyl amine; THF is tetrahydrofuran; TFA istrifluoroacetic acid; TLC is thin-layer chromatography; TosCl isp-toluene sulfonyl chloride; t-BuOK is potassium tert-butoxide; andX-Phos Second Generation Precatalyst ischloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),THF adduct.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare either commercially available or made by known procedures in theliterature or as illustrated. The present invention further providesprocesses for the preparation of compounds of structural formula I asdefined above. In some cases the order of carrying out the foregoingreaction schemes may be varied to facilitate the reaction or to avoidunwanted reaction products. The following examples are provided for thepurpose of illustration only and are not to be construed as limitationson the disclosed invention. All temperatures are degrees Celsius unlessotherwise noted.

In Scheme I, the amino group in 2-amino-4-bromopyridine (1-1) isprotected by a bis-p-methoxybenzyl (PMB) group by reaction of (1-1) withPMB-Cl in the presence of strong base to afford (1-2). The protectedpyridyl derivative (1-2) is reacted with N-iodosuccinimide (NIS) toyield the 5-iodopyridine (1-3). Under mild Suzuki reaction conditionswith a vinyl-tin reagent, the iodo derivative (1-3) is converted to the5-vinylpyridine (1-4). Under more vigorous Suzuki reaction conditions,(1-4) is reacted with tributyl-3-propenyl tin to afford the 4-allyl,5-vinyl pyridyl compound (1-5). Under ring closure metathesis (RCM)conditions employing Grubbs catalyst, (1-5) is converted to theaza-indene derivative (1-6). Reaction of the double bond in (1-6) withethyl diazoacetate in the presence of a rhodium catalyst affords theaza-tricyclic derivative (1-7). Removal of the PMB protecting groups in(1-7) and subsequent diazotization/hydrolysis yields thehydroxyl-aza-tricyclic key intermediate (1-9).

In Scheme II, bromoester (2-1) is hydrolysed to acid (2-2) with a basesuch as lithium hydroxide then reduced to alcohol (2-3) with a reducingagent such as borane. The benzylic alcohol (2-3) is then converted tomesylate (2-4) using mesyl chloride in the presence of a base such astriethylamine then reacted with key intermediate (1-9) in the presenceof silver carbonate to yield bromo intermediate (2-5). This bromointermediate (2-5) can be used as is or it can be converted into anotherintermediate, key boronate intermediate (2-6), usingbis(pinacolato)diboron in the presence of a palladium catalyst such asPd(dppf)Cl₂.

In Scheme III, bromophenol (3-1) is treated with tosylate (3-2) in thepresence of a base such as K₂CO₃ to afford bromophenoxide (3-3). Thisintermediate (3-3) can be cross-coupled with key intermediate (2-6)under Suzuki conditions in the presence of a palladium catalyst such asPd(dtbpf)Cl₂ to provide ester (3-5). Alternatively, intermediate (3-3)can be converted into boronate intermediate (3-4) usingbis(pinacolato)diboron in the presence of a palladium catalyst such asPd(dppf)Cl₂, and intermediate (3-4) can in turn be cross-coupled withkey intermediate (2-5) under Suzuki conditions in the presence of apalladium catalyst such as Pd(dtbpf)Cl₂ to provide ester (3-5). Ester(3-5) is then hydrolysed using base such as sodium or lithium hydroxideto yield the compound of Formula (I).

Intermediate 14-Hydroxy-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]indene-1-carboxylicacid ethyl ester

Step A. (4-Bromo-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine

To a suspension of sodium hydride (60% in oil, 93 g, 2.32 mol) in DMF(1.8 L), was added 2-amino-4-bromopyridine (100 g, 0.58 mol) in DMF (500mL) slowly at 0° C. Then the resulting mixture was allowed to stir atr.t. for 0.5 h under N₂ protection. PMBC1 (227 g, 1.45 mol) was added tothe reaction mixture and the reaction was maintained at 0-10° C. Afteraddition, the mixture was allowed to stir at r.t. for 2 h. Then themixture was poured into ice water carefully. The resulting solidprecipitate was collected and washed with PE (150 mL×3), and thefiltrate was concentrated to afford the title compound. ¹HNMR (400 MHz,CDCl₃) δ: 7.99 (d, 1H, J=2.4 Hz), 7.12 (d, 4H, J=4.0 Hz), 6.84 (d, 4H,J=4.0 Hz), 6.71 (d, 1H, J=2.4 Hz), 6.64 (s, 1H), 4.66 (s, 4H), 3.79 (s,6H).

Step B. (4-Bromo-5-iodo-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine

To a stirred solution of product from Step A (140 g, 0.34 mol) in DMF(2.8 L), was added NIS (115 g, 0.51 mmol) in several portions. Theresulting mixture was heated to 40° C. and stirred for 24 h. The mixturewas cooled and poured into ice water and stirred constantly. Theresulting solid precipitate was collected and washed with PE (100 mL×3).The filtrate was concentrated under vacuum to afford the title compound.¹HNMR (400 MHz, CDCl₃) δ: 8.40 (s, 1H), 7.09 (d, 4H, J=4.0 Hz),6.84-6.80 (m, 5H), 4.62 (s, 4H), 3.78 (s, 6H).

Step C. (4-Bromo-5-vinyl-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine

To a stirred solution of product from Step B (144 g, 267 mmol) intoluene (2 L), was added tributyl (vinyl) tin (85 g, 267 mmol),Pd(PPh₃)₄ (15.4 g, 13.4 mmol), KF (31 g, 534 mmol). The resultingmixture was heated to reflux for 18 h under N₂. The mixture was thencooled and KF (300 mL, 2 mol/L) was added. The reaction mixture wasstirred for 20 minutes, and then filtered. The filtrate was separated,and the resulting organic layer was collected and evaporated undervacuum to give the crude product, which was purified by columnchromatography on silica gel (eluting with PE:EA=20:1) to give the titlecompound. ¹HNMR (400 MHz, CDCl₃) δ: 8.36 (s, 1H), 7.13 (d, 4H, J=4.0Hz), 6.86-6.82 (m, 5H), 6.68 (s, 1H), 5.59 (d, 1H, J=8.0 Hz), 5.17 (d,1H, J=6.4 Hz), 4.67 (s, 4H), 3.78 (s, 6H).

Step D. (4-Allyl-5-vinyl-pyridin-2-yl)-bis-(4-methoxy-benzyl)-amine

To a stirred solution of the product from Step C (90 g, 205 mmol) in THF(2 L), was added Cs₂CO₃ (134 g, 410 mmol), Pd(dppf)Cl₂ (7.5 g, 10.3mmol), and allyltributyltin (136 g, 410 mmol). The resulting mixture washeated to reflux for 18 h under N₂. Then the mixture was cooled, and KF(300 mL, 2 mol/L) was added. The reaction mixture was stirred for 20minutes. The mixture was filtered and the filtrate was separated. Theresulting organic layer was collected and evaporated under vacuum togive the crude product, which was purified by chromatography over silicagel (eluting with PE:EA=30:1) to give the title compound. ¹HNMR (400MHz, CDCl₃) δ: 8.34 (s, 1H), 7.14 (d, 4H, J=4.0 Hz), 6.83 (d, 4H, J=4.0Hz), 6.75 (dd, 1H, J=11.2 and 17.6 Hz), 6.29 (s, 1H), 5.86-5.79 (m, 1H),5.53 (d, 2H, J=8.0 Hz), 5.14-4.96 (m, 3H), 4.69 (s, 4H), 3.79 (s, 6H),3.27 (d, 2H, J=4.0 Hz). MS (ESI) m/e (M+H⁺): 440.1

Step E: Bis-(4-methoxy-benzyl)-(5H-[2]pyrindin-3-yl)-amine

To a stirred solution of the product from Step D (55 g, 138 mmol) in DCM(700 mL), was added Grubbs reagent (II) (3.5 g, 4.14 mmol) in oneportion. Then the resulting mixture was heated to reflux for 3 h underN₂. The mixture was then cooled and used in the next step directly. MS(ESI) m/e (M+H⁺): 373.2.

Step F:4-[Bis-(4-methoxy-benzyl)-amino]-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]-indene-1-carboxylicacid ethyl ester

To a stirred solution of the product from Step E (52 g, 138 mmol) in DCM(0.7 L), was added Rh(OAc)₂ (1.6 g, 6.9 mmol) in one portion and themixture was stirred for 15 minutes. Then ethyl diazoacetate (126 g, 1.1mol) was added slowly to the mixture under gentle reflux conditions over3 h. The resulting mixture was allowed to stir at r.t for 1 h. Thereaction mixture was evaporated under vacuum to give the crude product,which was purified by column chromatography over silica gel (PE:EA=10:1)to give a cis-isomeric mixture of title compound as a racemate. Theracemic mixture was separated by chiral column chromatography (elutingwith PE:EA) to give the title compound. ¹HNMR (400 MHz, CD₃OD) δ: 8.01(s, 1H), 7.08 (d, 4H, J=4.0 Hz), 6.81. (d, 4H, J=4.0 Hz), 6.45 (s, 1H),4.63 (s, 4H), 4.07 (dd, 2H, J=7.2 and 14.4 Hz), 3.74 (s, 6H), 3.13 (dd,1H, J=6.0 and 12.0 Hz), 2.89 (d, 1H, J=8.0 Hz), 2.84 (d, 1H, J=2.4 Hz),2.33-2.30 (m, 1H), 1.28-1.15 (m, 4H). MS (ESI) m/e (M+H⁺): 459.1.

Step G:4-Amino-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]indene-1-carboxylic acidethyl ester

To a stirred solution of product from Step F (19 g, 41.4 mmol) in DCM(130 mL), was added TFA (130 mL) in one portion. Then the resultingmixture was stirred at r.t overnight. LCMS showed reagent was consumedcompletely. The mixture was evaporated under vacuo to give the titlecompound, which was used in the next step directly. MS (ESI) m/e (M+H⁺):219.1.

Step H:4-Hydroxy-1,1a,6,6a-tetrahydro-3-aza-cyclopropa[a]indene-1-carboxylicacid ethyl ester

To a stirred solution of product from Step G (23 g, crude) in H₂SO₄ (200mL, 15%), was added NaNO₂ (14.4 g, 209 mmol) in portions at 0° C. Thenthe resulting mixture was allowed to stir at r.t for 2 h. LCMS showedreagent was consumed. The mixture was filtered, the solid filtered waspurified by column (DCM: MeOH=20:1), the filtrate was basified with 2NNaOH to pH=5-6, then aqueous NaHCO₃ was added to adjust the pH=7, thenextracted with DCM (300 mL×3), washed with brine, dried over Na₂SO₄,concentrated to afford the title compound. ¹HNMR (400 MHz, CDCl₃) δ:12.52 (s, 1H), 7.28 (s, 1H), 6.38. (s, 1H), 4.14 (dd, 2H, J=7.2 and 14.4Hz), 3.18 (dd, 1H, J=6.0 and 12.0 Hz), 2.94 (d, 1H, J=8.8 Hz), 2.77 (dd,1H, J=2.4 and 6.4 Hz), 2.43-2.39 (m, 1H), 1.28-1.25 (m, 4H). MS (ESI)m/e (M+H⁺): 220 (M+H⁺).

Intermediate 2 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate

To a solution of 3-methylbutan-1,3-diol (10.0 g, 96.1 mmol) in DCM (100mL) was added 4-methylbenzene-1-sulfonyl chloride (20.1 g, 106 mmol) andTEA (24.3 g, 240 mmol). The reaction mixture was stirred at roomtemperature for 12 h. Then the mixture was extracted with DCM (150mL×3). The combined organic layers were washed with water and brine,dried over MgSO₄, and filtered. The filtrate was concentrated underreduced pressure. The resulting residue was purified by chromatographyover silica gel (eluting with PE:EA=5:1) to give the title compound.

Intermediate 3 2-(3-hydroxyoxetan-3-yl)ethyl 4-methylbenzenesulfonate

Step A: 3-allyloxetan-3-ol

To a stirred solution of 3-oxetanone (10.0 g, 139 mmol) in THF (80 mL),was added allylmagnesium bromide (210 mL, 209 mmol) dropwise at −60° C.under N₂. Then the reaction mixture was stirred at −50 to −60° C. for 3h. The reaction was neutralized with 2 N HCl, extracted with EtOAc (100mL×3), and the combined organic layers were washed with brine, driedover Na₂SO₄, and concentrated to afford a crude product, which waspurified by chromatography over silica gel (eluting with PE:EA=5:1) togive the title compound as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ:5.89-5.79 (m, 1H), 5.25 (s, 1H), 5.21 (d, J=2.4 Hz, 1H), 4.61 (d, J=6.7Hz, 2H), 4.51 (d, J=7.0 Hz, 2H), 2.62 (d, J=3.6 Hz, 3H), 2.41 (s, 1H).

Step B: 2-(3-hydroxyoxetan-3-yl)acetaldehyde

Ozone was bubbled into a solution of the product from Step A (2.00 g,17.6 mmol) in DCM (30 mL) at −50° C. for 5 min After excess O₃ waspurged by N₂ for 10 min, Me₂S (6.00 g, 100 mmol) was added and thereaction was stirred for 3 h at r.t. The reaction mixture was evaporatedunder vacuum to afford the title compound, which was used in the nextstep without purification.

Step C: 3-(2-hydroxyethyl)oxetan-3-ol

To a stirred suspension of LiAlH₄ (1.0 g, 26 mmol) in THF (50 mL), wasadded dropwise the product from Step B (3 g, crude) in THF (20 mL) at 0°C. The resulting mixture was stirred for 2 h at 0° C., then quenched byslow addition of H₂O (4 mL), followed by the addition of 15% aqueousNaOH (1 mL) After stirring at r.t for 30 min, the resulting solid wasremoved by filtration. The filtrate was then concentrated to dryness togive the title compound. ¹HNMR (400 MHz, CDCl₃) δ: 4.64 (d, J=6.7 Hz,2H), 4.49 (d, J=7.0 Hz, 2H), 4.08 (s, 1H), 3.92 (q, J=5.0 Hz, 2H), 2.29(br. s., 1H), 2.14 (t, J=5.3 Hz, 2H).

Step D: 2-(3-hydroxyoxetan-3-yl)ethyl 4-methylbenzenesulfonate

To a stirred suspension of the product from Step C (300 mg, 2.55 mmol)in DCM (4 mL) was added pyridine (0.95 mL, 10.2 mmol), TosCl (728 mg,3.83 mmol) portionwise, and DMAP (30 mg). The resulting mixture wasallowed to stir at r.t. overnight. The reaction mixture was then dilutedwith H₂O (10 mL), extracted with EtOAc (30 mL×3), and the organic layerswere washed with brine, dried over Na₂SO₄, and concentrated to afford acrude product, which was purified by chromatography over silica gel(eluting with PE:EA=1:1) to give the title compound. ¹HNMR (400 MHz,CDCl₃) δ: 7.77 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 4.62-4.48 (m,4H), 4.22 (t, J=6.1 Hz, 2H), 2.95 (d, J=3.9 Hz, 1H), 2.45 (s, 3H), 2.21(t, J=6.1 Hz, 2H).

Intermediate 4 4,4-difluoro-3-hydroxy-3-methyl-4-(phenylsulfonyl)butyl4-methylbenzenesulfonate

Step A: 4,4-difluoro-3-methyl-4-(phenylsulfonyl)butane-1,3-diol

To a solution of ((difluoromethyl)sulfonyl)benzene (10.0 g, 52.0 mol)and 4-hydroxybutan-2-one (6.87 g, 78.0 mol) under nitrogen in anhydrousTHF (100 mL) at −78° C. was added dropwise KHMDS (78.0 mL, 78.0 mmol).The reaction mixture was stirred at −78° C. for 3 hours, and thenquenched with water at −78° C. The reaction mixture was extracted withEtOAc (100 mL×3). The combined organic layers were washed with water andbrine, dried over MgSO₄, and filtered. The filtrate was concentratedunder reduced pressure to give the title compound, which was usedwithout purification in the next step. MS (ESI) m/e (M+H⁺): 281.

Step B: 4,4-difluoro-3-hydroxy-3-methyl-4-(phenylsulfonyl)butyl4-methylbenzene sulfonate

To a solution of the product from Step A (15.4 g, 55.0 mmol) in DCM (200mL) was added Et₃N (16.7 g, 165 mmol) and 4-methylbenzene-1-sulfonylchloride (10.5 g, 55.0 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 16 h. Then the reaction mixture wasdiluted with DCM (150 mL), and the organic layer was washed with waterand brine, dried over MgSO₄, and filtered. The filtrate was concentratedunder reduced pressure. The resulting residue was purified bychromatography over silica gel (eluting with PE:EA=15:1) to give thetitle compound. MS (ESI) m/e (M+H⁺): 435.

Intermediate 5 (5aR,6S,6aS)-ethyl3-((5-bromo-2-fluoro-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Step A: methyl 2-fluoro-4-(trifluoromethyl)benzoate

To a mixture of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (5.0 g, 0.02mol) in EtOH (10 mL) was added Pd(dppf)Cl₂ (1.46 g, 0.2 mmol) and AcONa(3.37 g, 0.041 mol), and the resulting mixture was stirred at 80° C.under an atmosphere of CO (50 psi) for 8 hours. The mixture was thenfiltrated and the filtrate was partitioned with ethyl acetate and water.The aqueous layer was separated and extracted with ethyl acetate twice.The combined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated in vacuo. The resulting residue was purified bycolumn chromatography on silica gel (eluting with PE:EA=10:1) to givethe title compound. ¹H NMR (400 MHz, CDCl₃) g: 8.04-8.08 (t, 1H, J=7.6Hz), 7.49-7.47 (d, 1H, J=8.0 Hz), 7.43-7.40 (d, 1H, J=10.4 Hz),4.44-4.40 (q, 2H, J=7.2 Hz), 1.43-1.38 (t, 3H, J=7.2 Hz).

Step B: ethyl 2-fluoro-5-nitro-4-(trifluoromethyl)benzoate

To a stirred solution of the product from Step A (120 g, 0.51 mol) inconcentrated H₂SO₄ (0.5 L), was added dropwise fuming HNO₃ (50 ml) at 0°C. The resulting mixture was stirred at 25° C. for 1 h, then cooled andpoured into ice water and stirred. The solid that precipitated wascollected and washed with PE (100 mL×3). The filtrate was concentratedunder vacuum to afford the title compound. ¹HNMR (400 MHz, CDCl₃) δ:8.54-8.45 (d, 1H, J=6.8 Hz), 7.63-7.60 (d, 1H, J=10.4 Hz), 4.48-4.43 (q,2H, J=7.2 Hz), 1.55-1.39 (t, 3H, J=7.2 Hz).

Step C: ethyl 5-amino-2-fluoro-4-(trifluoromethyl)benzoate

To a solution of the product from Step B (80 g, 0.28 mol) in MeOH (1 L)was added Pd/C (8 g). The mixture was degassed via vacuum and purgedwith H₂ several times, then the mixture was stirred under a H₂ balloonfor 16 hours at room temperature. The mixture was filtered; and thefiltrate was concentrated to give the title compound. MS (ESI) m/e(M+H⁺): 273.1, 293.2.

Step D: ethyl 5-bromo-2-fluoro-4-(trifluoromethyl)benzoate

To a stirred solution of the product from Step C (60 g, 0.24 mol) in ACN(600 mL), was added CuBr₂ (59 g, 0.26 mol) and isopentyl nitrite (36 g,0.31 mol). The resulting mixture was stirred at 25° C. for 18 h underN₂. The mixture was then cooled and filtered, and the filtrate wasseparated. The organic layer was collected and evaporated under vacuumto give a crude product, which was purified by column chromatographyover silica gel (eluting with PE:EA=30:1) to give the title compound.¹HNMR (400 MHz, CDCl₃) δ: 8.24-8.05 (d, 1H, J=6.8 Hz), 7.53-7.50 (d, 1H,J=10.4 Hz), 4.48-4.43 (q, 2H, J=7.2 Hz), 1.45-1.39 (t, 3H, J=7.2 Hz).

Step E: 5-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid

To a solution of the product from Step D (17.5 g, 55.7 mmol) in EtOH/H₂O(200/20 mL) was added LiOH (12 g, 0.28 mol). The reaction mixture wasstirred at room temperature for 18 h. Then HCl (2 mol/L) was added tothe reaction to adjust the pH to 5. The reaction mixture wasconcentrated under vacuum to remove the EtOH, and the remaining mixturewas extracted with EtOAc (50 mL×3). The combined organic layers wereconcentrated to afford the title compound.

Step F: (5-bromo-2-fluoro-4-(trifluoromethyl)phenyl)methanol

To a solution of the product from Step E (17.08 g, 59.7 mmol) in THF(170 mL) was added BH₃(Me₂S) (18 mL) at 0° C. The reaction was stirredat 17-19° C. for 18 h. Then the reaction was quenched with MeOH at 0° C.The reaction mixture was concentrated and the resulting crude residuewas purified by chromatography over silica gel (eluting with PE:EA=5:1)to give the title compound.

Step G: 5-bromo-2-fluoro-4-(trifluoromethyl)benzyl methanesulfonate

To a solution of the product from Step F (4 g, 14.65 mmol) in DCM (20ml) was added TEA (2.22 g, 22 mmol). The reaction mixture was cooled inan ice bath, then MsCl (1.5 g, 22 mmol) was added dropwise to thereaction. The reaction was stirred at 0° C. for 20 min, then water (30mL) was added to the reaction mixture at 0° C. The resulting mixture wasextracted with DCM (10 mL×3). The combined organic layers was dried overNa₂SO₄ and concentrated under vacuum to give the title compound.

Step H: (5aR,6S,6aS)-ethyl3-((5-bromo-2-fluoro-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To a solution of the product from Step G (5 g crude) in toluene (50 ml)were added Intermediate 1 (3.1 g, 14.1 mmol) and Ag₂CO₃ (11.66 g, 42.3mmol). The reaction was stirred at 100° C. for 18 h. Then the reactionmixture was cooled to room temperature and filtered. The filtrate wasconcentrated in vacuo and the crude was purified by chromatography oversilica gel (eluting with PE:EA=10:1) to give the title compound. ¹HNMR(400 MHz, MeOH-d₄) δ: 8.05 (s, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.39 (d,J=9.8 Hz, 1H), 6.64 (s, 1H), 5.41 (s, 2H), 4.13 (q, J=7.0 Hz, 2H), 3.23(dd, J=6.3, 18.4 Hz, 1H), 3.00 (d, J=18.4 Hz, 1H), 2.91 (d, J=5.1 Hz,1H), 2.48-2.40 (m, 1H), 1.25 (t, J=7.2 Hz, 3H), 1.22 (d, J=3.1 Hz, 1H).MS (ESI) m/e (M+H⁺): 474, 476.

Intermediate 65aR,6S,6aS)-ethyl3-((2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Bis(pinacolato)diboron (0.803 g, 3.16 mmol), potassium acetate (0.414 g,4.22 mmol), Pd(dppf)Cl₂ (0.154 g, 0.211 mmol), and Intermediate 5 (1.00g, 2.11 mmol) were dissolved in DMF (0.8 mL) and dioxane (2.5 mL), thenplaced in a sealed tube and heated in a microwave oven at 150° C. for 30min. The reaction mixture was cooled and the solvent was evaporatedunder reduced pressure. The resulting residue was purified by columnchromatography on silica gel (eluting with PE:EA=5:1) to give the titlecompound as a colorless gum. ¹HNMR (400 MHz, CDCl₃) δ: 8.12-8.05 (m,1H), 7.94-7.87 (m, 1H), 7.44-7.36 (m, 1H), 6.66-6.61 (m, 1H), 5.41 (s,2H), 4.20-4.12 (m, 2H), 3.28-3.19 (m, 1H), 3.06-2.90 (m, 2H), 2.51-2.41(m, 1H), 1.36 (s, 12H), 1.28 (t, J=6.3 Hz, 3H), 1.24-1.21 (m, 1H).

Intermediate 7 5aR,6S,6aS)-ethyl3-((5-bromo-4-(difluoromethyl)-2-fluorobenzyl)oxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Step A: 5-bromo-2-fluoro-4-methylbenzoic acid

2-fluoro-4-methylbenzoic acid (10 g, 64.9 mmol) was added in portions toa mixture of bromine (145 g, 908 mmol) and iron (1.812 g, 32.4 mmol),and the reaction mixture was stirred in a sealed vial for 28 h. Thereaction mixture was then poured into aqueous saturated sodiumthiosulfate and extracted with ethyl acetate (50 ml×2). The combinedethyl acetate extracts were washed with brine, dried over magnesiumsulfate and concentrated. The resulting residue was suspended in ethylacetate and the insoluble impurity was filtered off. Then the filtratewas concentrated to dryness under vacuum to give the title compound as ayellow solid, which was used in the next step without furtherpurification.

Step B: methyl 5-bromo-2-fluoro-4-methylbenzoate

To a mixture of product from Step A (16 g, 68.7 mmol) in MeOH (20 ml)was added concentrated sulfuric acid (0.673 g, 6.87 mmol) at roomtemperature. The mixture was stirred at reflux overnight. After coolingdown, the solvent was evaporated off to give a crude oil. The oil waspurified by column chromatography over silica gel (eluting withPE:EA=20:1) to give the title compound as a colorless oil. ¹HNMR (400MHz, CDCl₃) δ: 8.09 (d, J=7.2 Hz, 1H), 7.04 (d, J=11.2 Hz, 1H), 3.93 (s,3H), 2.43 (s, 3H).

Step C: methyl 5-bromo-4-(dibromomethyl)-2-fluorobenzoate

To a mixture of the product from Step 13 (1.6 g, 6.425 mmol) in CCl₄ (20mL) was added NBS (3.46 g, 19.43 mmol) and benzoic peroxyanhydride(0.157 g, 0.648 mmol). The reaction mixture was stirred at 90° C.overnight. The mixture was then cooled and filtrated through a Celite™pad and the insoluble solid was washed with PE twice. The combinedorganic layers were concentrated in vacuo to give a crude oil, which waspurified by column chromatography over silica gel (eluting withPE:EA=20:1) to give the title compound as a light yellow oil. ¹HNMR (400MHz, CDCl₃) δ: 8.10 (d, J=7.0 Hz, 1H), 7.82 (d, J=11.2 Hz, 1H), 6.95 (s,1H), 3.96 (s, 3H).

Step D: methyl 5-bromo-2-fluoro-4-formylbenzoate

To a suspension of the product from Step C (2.5 g, 6.18 mmol) in THF (20mL) and water (7 mL) was added AgNO₃ (3.15 g, 18.53 mmol). The reactionmixture was stirred at 80° C. for 2 hours. After cooling down, themixture was filtrated through Celite™, washed with DCM, and the combinedorganic layers were concentrated in vacuo. The resulting residue waspurified by flash chromatography over silica gel (eluting withPE/EA=10%) to give the title compound as a yellow solid, which was usedin the next step without further purification.

Step E: methyl 5-bromo-4-(difluoromethyl)-2-fluorobenzoate

To a solution of the product from Step D (0.5 g, 1.915 mmol) in DCM (5.0mL), in an ice bath, was added DAST (0.72 g, 4.8 mmol). The reactionmixture was allowed to warm to r.t. and stirred at room temperatureovernight. The reaction was then poured into ice water, and extractedwith DCM (10 mL×3). The combined organic layers were washed with brine,dried over Na₂SO₄ and concentrated in vacuo to give the title compoundas a light yellow oil, which was used in the next step without furtherpurification. ¹HNMR (400 MHz, CDCl₃) δ: 8.18 (d, J=6.6 Hz, 1H), 7.47 (d,J=10 Hz, 1H), 6.85 (m, 1H), 3.95 (s, 3H).

Step F: (5-bromo-4-(difluoromethyl)-2-fluorophenyl)methanol

To a mixture of the product from Step E (0.3 g, 1.060 mmol) and NaBH₄(0.120 g, 3.18 mmol) in THF (3.0 mL), in an ice bath, was added MeOH(0.1 mL) The reaction mixture was stirred at 60° C. for 2 hrs, and thenpartitioned between H₂O and EtOAc. The aqueous layer was separated andextracted by EtOAc twice. The combined organic layers were washed withbrine, dried over Na₂SO₄, and concentrated in vacuo to give a crude oil,which was purified by chromatography over silica gel (eluting withPE:EA=5:1) to give the title compound as a light yellow oil.

Step G: 1-bromo-5-(bromomethyl)-2-(difluoromethyl)-4-fluorobenzene

To a solution of the product from Step F (200 mg, 0.784 mmol) in DCM (3mL) at 0° C. was added tribromophosphine (212 mg, 0.784 mmol). Themixture was stirred at 0° C. for 1 hour. The reaction was then quenchedwith H₂O and extracted with DCM twice. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated in vacuo to givethe title compound as a colorless oil, which was used in the next stepwithout purification.

Step H: (5aR,6S,6aS)-ethyl3-((5-bromo-4-(difluoromethyl)-2-fluorobenzyl)oxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To a solution of the product from Step G (130 mg, 0.409 mmol) in toluene(2 mL), was added Ag₂CO₃ (169 mg, 0.613 mmol) and Intermediate 1 (98 mg,0.409 mmol). The mixture was stirred at 120° C. for 4 hours. Then thereaction mixture was filtrated through a Celite™ pad and washed withDCM. The combined filtrates were concentrated in vacuo to give aresidue, which was purified by chromatography on silica gel (elutingwith PE:EA=5:1) to give the title compound as a colorless oil. MS (ESI)m/e (M+H⁺): 456.2.

Intermediate 8 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate

Step A: 3-(methylthio)propyl 4-methylbenzenesulfonate

To a solution of the 3-(methylthio)propan-1-ol (50 g, 0.47 mol) andtriethylamine (95 g, 0.94 mol) in DCM (500 mL) was added TsCl (90 g,0.47 mol) portionwise at 0° C. After completion of addition, thereaction mixture was allowed to warm to room temperature slowly andstirred at this temperature for 16 h. Then the reaction was quenchedwith 1N HCl to adjust the pH to pH 7-8, and the mixture was extractedthree times with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue which was purified by chromatography over silica gel (elutingwith PE:EA=5:1) to afford the title compound.

Step B: 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate

To a solution of product from Step A (35 g, 135 mmol) in dry DCM (400mL) in an ice-bath was added MCPBA (46.5 g, 270 mmol) portionwise. Theresulting mixture was stirred at 0° C. for 1 h, and then warmed to theroom temperature and stirred for 20 h. The reaction was quenched byaddition of aqueous solution of NaHSO₃ and the DCM layer was washed withNa₂CO₃ (aq.), water and brine, respectively, and concentrated to afforda residue, which was purified by chromatography on silica gel (elutingwith PE:EA=3:1) to give the title compound.

Intermediate 9 (5aR,6S,6aS)-tert-butyl3-hydroxy-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Step A: (E)-methyl5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-chloroisonicotinate

To a solution of 5-bromo-2-chloroisonicotinic acid (Combi-Blocks, 100 g,423 mmol) in THF (200 mL) and toluene (800 mL) was added DMF (1.6 mL,21.15 mmol). To the resulting slurry was added slowly oxalyl chloride(47 mL, 529 mmol). The reaction was stirred over the weekend at roomtemperature. Then MeOH (100 mL) was added slowly while cooling in awater bath. After 2 h at room temperature, aqueous K₂HPO₄ (1 M, 423 mL,423 mmol) was added slowly while cooling in a water bath. The layerswere separated and the aqueous layer was extracted with toluene (1×250mL) The combined organic layers were filtered through Solca-Floc™cellulose, then washed with water (1×200 mL), dried over MgSO₄ andconcentrated in vacuo to give the crude methyl ester intermediate. Tothe methyl ester intermediate in toluene (2 L) was addedchloro[tris(2-methylphenyl)phosphine][2-(2′-amino-1,1′-biphenyl)]palladium(II)(2.6 g, 4.23 mmol, 1%) and N,N-dicyclohexylmethylamine (226 mL, 1057mmol). The reaction was degassed for 1 h, then t-butyl acrylate wasadded in a single portion and the reaction mixture was heated to 80° C.overnight. Then additionalchloro[tris(2-methylphenyl)phosphine][2-(2′-amino-1,1′-biphenyl)]palladium(II)(1.3 g, 2.12 mmol, 0.5%) was added and the reaction was heated at 80° C.for 3 h. The reaction mixture was then cooled to room temperature andquenched with water (500 mL) The organic layer was separated, washedwith saturated brine (1×500 ml), then filtered through a plug of silicagel (150 g) and rinsed with 20% EtOAc in hexanes. The filtrate wasconcentrated in vacuo to give a crude oil, which was recrystallized fromEtOAc in hexane (1:1) at −10° C. to provide the title compound. MS (ESI)m/e (M+H⁺): 242.2.

Step B: (E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-chloroisonicotinicacid

To a solution of (E)-methyl5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-chloroisonicotinate (1 g, 3.36mmol) in THF (10 ml) was added a solution of lithium hydroxide hydrate(0.155 g, 3.69 mmol) in water (2 ml), and the reaction was stirred atroom temperature overnight. The reaction was then concentrated in vacuoand the resulting residue was diluted with 5 mL water, and slowlyacidified with ice-cold 1N HCl solution (4.03 mL) The resulting whitesolid was filtered and dried under high vacuum to provide the titlecompound. MS (ESI) m/e (M+H⁺): 284.2.

Step C: (E)-tert-butyl3-(6-chloro-4-((E)-2-chloro-2-hydrazonoacetyl)pyridin-3-yl)acrylate

DMF (25 μl, 0.323 mmol) was added to a suspension of(E)-5-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-2-chloroisonicotinic acid(1.73 g, 6.10 mmol) in dichloromethane (55 mL) and the reaction mixturewas stirred at room temperature for 1 hour. The reaction mixture wasthen concentrated in vacuo, and co-evaporated with 1,2-dichloroethane.Then DCM (24 ml) was added to the resulting residue, and the resultingsolution was added to a solution of (isocyanoimino)-triphenylphosphorane(2.77 g, 9.15 mmol) in DCM (14 mL) over 10 min. The reaction mixture wasstirred at room temperature for 2 hours. Then water (6.6 ml, 366 mmol)was added and the mixture was stirred at room temperature overnight.Then the organic layer was separated, dried over MgSO₄ and concentratedin vacuo to provide a residue, which was purified by columnchromatography over silica gel (eluting with EtOAc:hexanes=0:100 to30:70) to give the title compound. MS (ESI) m/e (M+H⁺): 344, 346, 348.

Step D: (E)-tert-butyl3-(6-chloro-4-(2-diazoacetyl)pyridin-3-yl)acrylate

Anhydrous zinc bromide (325 mg, 1.443 mmol) was added to a solution ofcompound (E)-tert-butyl3-(6-chloro-4-((E)-2-chloro-2-hydrazonoacetyl)pyridin-3-yl)acrylate(2.09 g, 6.07 mmol) in DCM (20 ml), followed by the dropwise addition ofdiisopropylethylamine (1.2 ml, 8.42 mmol). The reaction was stirred atroom temperature for 1 hour, and then diluted with EtOAc. The organiclayer was washed with 1% ethylenediamine tetraacetic acid tetrasodiumsalt, dried over anhydrous MgSO₄, and concentrated in vacuo. Theresulting crude residue was purified by column chromatography oversilica gel (eluting with EtOAc:hexanes=0:100 to 30:70) to give the titlecompound. MS (ESI) m/e (M+H⁺): 308, 310.

Step E: (5aR,6R,6aS)-tert-butyl3-chloro-5-oxo-5,5a,6,6a-tetrahydrocyclopropa-[4,5]cyclopenta-[1,2-c]pyridine-6-carboxylate

A solution of 2,2-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)acetonitrile(5.17 mg, 0.016 mmol), copper(I)trifluoromethanesulfonate toluenecomplex (3.36 mg, 6.50 μmol) and 2,6-di-tert-butylpyridine (29.2 μl,0.130 mmol) in THF (1 mL) was warmed to 25° C., then (E)-tert-butyl3-(6-chloro-4-(2-diazoacetyl)pyridin-3-yl)acrylate (400 mg, 1.300 mmol)in THF (3 mL) was added dropwise over 5 min. After 2.5 hours, thereaction mixture was diluted with EtOAc (3 mL) and MTBE (3 mL), washedwith 0.5 M aqueous citric acid (6 mL), and concentrated in vacuo toprovide a residue. The residue was purified by chromatography oversilica gel (eluting with EtOAc:hexanes=0:100 to 30:70) to provide thetitle compound. The ee of the title compound was upgraded to 95% bydissolution in EtOAc (6 mL/g) and removal of the racemate by filtration.MS (ESI) m/e (M+H⁺): 267.1.

Step F: (5aR,6S,6aS)-tert-butyl3-chloro-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta-[1,2-c]pyridine-6-carboxylate

Sodium borohydride (1.6 mg, 0.071 mmol) was added to a solution of(5aR,6R,6aS)-tert-butyl3-chloro-5-oxo-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta-[1,2-c]pyridine-6-carboxylate(20 mg, 0.071 mmol) in MeOH (0.4 mL) at 0° C. After 30 minutes, thereaction was quenched with saturated aqueous NH₄Cl and concentrated invacuo. The resulting residue was re-dissolved in MTBE and washed oncewith water. The organic layer was separated, dried over MgSO₄ andconcentrated in vacuo to give the alcohol intermediate. The alcoholintermediate was dissolved in THF (400 μL) and treated withtrifluoroacetic anhydride (2 equiv, 0.142 mmol) for 30 minutes. Thereaction was then cooled to 0° C., and concentrated aqueous HCl (5equiv, 0.355 mmol) was added, followed by the portionwise addition ofzinc dust (9.3 mg, 0.142 mmol) over 5 minutes. After stirring for 15minutes, the reaction was diluted with water and extracted with MTBEtwice. The combined organic layers were dried over MgSO₄ andconcentrated in vacuo to give a residue, which was purified by columnchromatography over silica gel (eluting with EtOAc:hexanes=10:90 to20:80) to provide the title compound. ¹H NMR (400 MHz, CDCl₃): δ 8.27(s, 1H), 7.05 (s, 1H), 3.18 (dd, J=6.35 Hz, 12.2 Hz, 1H), 2.97 (d,J=18.5 Hz, 1H), 2.83 (d, J=6.35 Hz, 1H), 2.37 (m, 1H), 1.39 (s, 9H),1.09 (br.s, 1H). MS (ESI) m/e (M+H⁺): 280.1.

Step G: (5aR,6S,6aS)-tert-butyl3-(2-(trimethylsilyl)ethoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To (5aR,6S,6aS)-tert-butyl3-chloro-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(0.5 g, 1.882 mmol), cesium carbonate (1.533 g, 4.70 mmol), andBrettPhos Precatalyst (0.075 g, 0.094 mmol) in a vial under nitrogen wasadded toluene (5 ml) and water (0.102 ml, 5.64 mmol). The reaction wasdegassed with bubbling nitrogen for 5 min, then2-(trimethylsilyl)ethanol (0.405 ml, 2.82 mmol) was added and thereaction was stirred at 80° C. for 16 hours. Then water (10 mL) andEtOAc (30 ml) were added and the aqueous layer was separated andextracted with EtOAc twice. The organic layers were combined and washedwith brine, dried over anhydrous Na₂SO₄, filtered, and concentrated invacuo to give the title compound, which was used in the next stepwithout further purification.

Step H: (5aR,6S,6aS)-tert-butyl3-hydroxy-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

To a solution of (5aR,6S,6aS)-tert-butyl3-(2-(trimethylsilyl)ethoxy)-5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(200 mg, 0.575 mmol) in acetonitrile (5 ml) was added water (5 ml),followed by phosphoric acid (0.146 ml, 2.014 mmol). The reaction wasstirred at room temperature for 19.5 h, then concentrated in vacuo. Theresulting residue was diluted with water and extracted withdichloromethane. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and the filtrate solvent was evaporated invacuo to give the title compound. ¹H NMR (400 MHz, CD3CL): 6: ppm 7.26(s, 1H), 6.38 (s, 1H), 3.14-3.24 (m, J=18.39, 6.26 Hz, 1H), 2.95-2.91(m, 1H), 2.70-2.69 (d, J=5.1 Hz, 1H), 2.32-2.31 (m, 1H), 0.83 (br. s.,1H). MS (ESI) m/e (M+H⁺): 248.1.

Intermediate 10 (5aR,6S,6aS)-tert-butyl3-((2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Intermediate 10 was prepared according to a procedure similar to theprocedure of Intermediate 6 starting from the appropriate startingmaterials and using the appropriate reagents. ¹H NMR (400 MHz, CDCl₃) δ:8.03-8.12 (m, 1H), 7.81-7.93 (m, J=7.43 Hz, 1H), 7.31-7.44 (m, J=10.17Hz, 1H), 6.51-6.65 (m, 1H), 5.38 (s, 2H), 3.14-3.24 (m, J=18.39, 6.26Hz, 1H), 2.93-3.05 (m, J=18.39 Hz, 1H), 2.80-2.88 (m, J=5.09 Hz, 1H),2.30-2.43 (m, 1H), 1.57 (s, 6H), 1.34 (s, 12H), 1.12 (br. s., 1H). MS(ESI) m/e (M+H⁺): 549.8.

Intermediate 11 (5aR,6S,6aS)-tert-butyl3-((2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Step A: 5-Bromo-2,4-difluoro-benzoic acid

To a stirred solution of 2,4-difluorobenzoic acid (40 g, 0.26 mol) inconcentrated H₂SO₄/TFA (1:5, 600 mL) at 0° C. was added NBS (45 g, 0.26mmol) in portions. The resulting mixture was heated at 60° C. overnight,then the reaction was cooled to room temperature and most of the TFA wasremoved by evaporation. The resulting residue was carefully partitionedbetween EtOAc and water. The aqueous layer was separated and extractedwith EtOAc twice. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄, and concentrated to give the crude product.The crude product was suspended in water and PE. The resulting solid wascollected by filtration, and then re-crystallized from ethanol to givethe title compound. ¹H NMR (400 MHz, CDCl₃) δ: 7.02 (dd, J=9.78, 8.61Hz, 1H), 8.28 (t, J=7.63 Hz, 1H).

Step B: (5-Bromo-2,4-difluoro-phenyl)-methanol

To a solution of 5-bromo-2,4-difluoro-benzoic acid (45.2 g, 190 mmol) inanhydrous THF (500 mL) cooled in an ice-bath was added (CH₃)₂S BH₃ (57mL, 570 mmol). The resulting mixture was allowed to stir at roomtemperature overnight. Then methanol (500 mL) was carefully added toquench the reaction, and the mixture was stirred at 60° C. for 1 h. Themixture was then acidified with HCl (1N) to pH-5 and extracted withEtOAc twice. The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄ and concentrated. The resulting residue waspurified via silica gel chromatography (PE/EtOAc=8/1) to give the titlecompound. 1H NMR (400 MHz, CDCl₃) δ: 4.77 (br. s., 2H), 6.95 (t, J=8.78Hz, 1H), 7.71 (t, J=7.53 Hz, 1H).

Step C: 1-Bromo-5-bromomethyl-2,4-difluoro-benzene

To a solution of (5-bromo-2,4-difluoro-phenyl)-methanol (35.2 g, 158mmol) in anhydrous DCM (800 mL) cooled in an ice-bath was added PBr₃(42.7 g, 157.8 mmol) dropwise. The reaction mixture was stirred at 0° C.for 1 h and at room temperature for 3 h. Then the reaction was quenchedwith water, and the aqueous layer was extracted with DCM twice. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and concentrated. The resulting residue was purified by columnchromatography on silica gel (PE/EtOAc=50/1) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ: 4.43 (s, 2H), 6.92 (s, 1H), 7.60(t, J=7.43 Hz, 1H).

Step D: (5aR,6S,6aS)-tert-butyl3-((5-bromo-2,4-difluorobenzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of 1-bromo-5-bromomethyl-2,4-difluoro-benzene (26.3 g, 77.4mmol), Intermediate 4 (19.1 g, 77.4 mmol) and Ag₂CO₃ (64 g, 232 mmol) indry toluene (600 mL) was heated at 110° C. for 12 h under a N₂atmosphere. Then the reaction mixture was cooled to room temperature,diluted with DCM (500 mL), and the resulting precipitate was filteredoff. The filtrate was concentrated and the resulting residue waspurified by column chromatography on silica gel (PE/EtOAc=10/1 to 5/1)to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ: 1.16 (br. s.,1H), 1.47 (s, 9H), 1.57 (s, 1H), 2.37-2.41 (m, 1H), 2.87 (d, J=5.09 Hz,1H), 2.98-3.03 (m, 1H), 3.22 (dd, J=18.39, 6.26 Hz, 1H), 5.35 (s, 2H)6.61 (s, 1H), 6.92 (t, J=8.80 Hz, 1H), 7.67-7.74 (m, 1H), 8.09 (s, 1H).MS (ESI) m/e (M+H⁺): 452.3/454.3.

Step E: (5aR,6S,6aS)-tert-butyl3-((2,4-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of (5aR,6S,6aS)-tert-butyl3-((5-bromo-2,4-difluorobenzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(3.0 g, 7.07 mmol), boronate4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.69 g,10.6 mmol), KOAc (1.39 g, 14.14 mmol), and Pd(dppf)Cl₂ (517 mg, 0.71mmol) in anhydrous DMF (2 mL)/anhydrous dioxane (6 mL) was charged in asealed tube under a N₂ atmosphere and heated at 150° C. under microwaveirradiation for 30 min. The mixture was then cooled to room temperatureand diluted with EtOAc (50 mL) The organic layer was separated, washedwith water and brine, dried over anhydrous Na₂SO₄ and concentrated. Theresulting residue was purified by column chromatography on silica gel(PE/EtOAc=3/1) to give the title compound. MS (ESI) m/e (M+H⁺): 500.2

Example 15aR,6S,6aS)-3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 4-(4-bromo-3-methylphenoxy)-2-methylbutan-2-ol

To a solution of Intermediate 2 (5.00 g, 19.4 mmol) in DMF (100 m) wasadded 4-bromo-3-methylphenol (3.00 g, 16.1 mmol) and K₂CO₃ (6.67 g, 48.3mmol) under nitrogen. The reaction mixture was stirred at roomtemperature for 12 h. The mixture was then extracted with EtOAc (50mL×3). The combined organic layers were washed with water and brine,dried over MgSO₄, and filtered. The filtrate was concentrated underreduced pressure. The resulting residue was purified by chromatographyover silica gel (eluting with PE:EA=20:1) to give the title compound. ¹HNMR (400 MHz, CDCl₃) δ: 7.11 (t, 2H, J=3.6 Hz), 6.77 (dd, 1H, J₁₃=8.8Hz, J₁₂=2.4 Hz), 4.12 (t, 2H, J=6.2 Hz), 2.31 (s, 3H), 2.04 (br, 1H),1.98 (t, 2H, J=6.4 Hz), 1.31 (s, 6H).

Step B:2-methyl-4-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butan-2-ol

To a solution of the product from Step A (3.50 g, 12.9 mmol) in dioxane(55 mL) was added bis(pinacolato)diboron (4.91 g, 19.3 mmol), KOAc (3.79g, 38.7 mmol) and Pd(dppf)Cl₂ (943 mg, 1.29 mmol) under nitrogen. Thereaction mixture was stirred at 90° C. for 3 h, then cooled to roomtemperature, and extracted with EtOAc (30 mL×3). The combined organiclayers were washed with water and brine, dried over MgSO₄, and filtered.The filtrate was concentrated under reduced pressure. The resultingresidue was purified by chromatography over silica gel (eluting withPE:EA=50:1) to give the title compound as white solid. ¹H NMR (400 MHz,CDCl₃) δ: 7.31 (d, 1H, J=2.8 Hz), 7.09 (d, 1H, J=8.4 Hz), 6.89 (dd, 1H,J₁₃=8.0 Hz, J₁₂=2.8 Hz), 4.20 (t, 2H, J=6.0 Hz), 2.56 (s, 3H), 1.99 (t,2H, J=6.0 Hz), 1.35 (s, 12H), 1.31 (s, 6H)

Step C: (5aR,6S,6aS)-ethyl3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

To a solution of Intermediate 5 (30.0 mg, 0.0634 mmol) in THF (1.5 mL)and H₂O (0.3 mL) were added the product from Step B (41.0 mg, 0.127mmol), K₃PO₄ (40.0 mg, 0.190 mmol) and Pd(dtbpf)Cl₂ (4.00 mg, 0.006mmol) under nitrogen. The reaction mixture was stirred at 100° C. for 3h, then cooled to room temperature, and extracted with EtOAc (3 mL×3).The combined organic layers were washed with water and brine, dried overMgSO₄, and filtered. The filtrate was concentrated under reducedpressure. The resulting residue was purified by chromatography oversilica gel (eluting with PE:EA=5:1) to give the title compound. MS (ESI)m/e (M+H⁺): 588.2.

Step D:(5aR,6S,6aS)-3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a solution of the product from Step C (31.0 mg, 0.0528 mmol) inTHF/MeOH/H₂O (1 mL/1 mL/1 mL) was added LiOH (22 mg, 0.528 mmol). Thereaction mixture was stirred at room temperature for 2 h. Then HCl (1mol/L) was added to the solution to adjust pH to 5 and the solution wasextracted with EtOAc (5 mL×3). The combined organic layers wereconcentrated under reduced pressure. The resulting residue was purifiedby preparative HPLC [preparative HPLC on a GILSON 281 instrument fittedwith a YMC-pack ODS-AQ (150×30 mm×5 um) column, using water andacetonitrile as the eluents. Mobile phase A: water, mobile phase B:acetonitrile. Gradient: 50-80% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B,13-15 min] to give the title compound. ¹H NMR (400 MHz, MeOD-d₄) δ: 8.08(s, 1H), 7.56 (d, 1H, J=10.6 Hz), 7.37 (t, 1H, J=6.4 Hz), 7.12 (d, 1H,J=8.4 Hz), 6.86-6.83 (m, 2H), 6.62 (s, 1H), 5.48 (s, 2H), 4.06 (t, 2H,J=6.8 Hz), 3.28 (s, 1H), 3.08 (d, 1H, J=18.8 Hz), 2.94 (d, 1H, J=6.4Hz), 2.45 (br, 1H), 1.92 (t, 2H, J=6.8 Hz), 1.84 (d, 3H, J=2.8 Hz), 1.23(s, 6H), 1.17 (s, 1H). MS (ESI) m/e (M+H⁺): 559.

Examples 2 to 4 was prepared in a similar manner to Example 1 using theappropriate intermediates and commercially available starting materials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+ 2

593 (5aR,6S,6aS)-3-((4- fluoro-2′-methyl-4′- (3-(methyl-sulfonyl)-propoxy)-6-(tri- fluoromethyl)-[1,1′- biphenyl]-3-yl)methoxy)-5,5a,6,6a- tetrahydrocyclo- propa[4,5]cyclopenta[1,2-c]pyridine-6- carboxylic acid 594 3

560 (5aR,6S,6aS)-3-((2- fluoro-5-(6-(3- hydroxy-3-methyl-butoxy)-2-methyl- pyridin-3-yl)-4- (trifluoromethyl)- benzyl)-oxy)-5,5a,6,6a-tetrahydro- cyclopropa[4,5] cyclopenta[1,2-c] pyridine-6- 561carboxylic acid 4

541 (5aR,6S,6aS)-3- ((6-(difluoro- methyl)-4-fluoro- 4′-(3-hydroxy-3-methyl-butoxy)- 2′-methyl-[1,1′- biphenyl]-3-yl) methoxy)-5,5a,6,6a-tetrahydrocyclo- propa[4,5] cyclopenta[1,2-c] pyridine-6- carboxylicacid 542

Example 5(5aR,6S,6aS)-3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 4-(4-bromophenoxy)-2-methylbutan-2-ol

To a solution of 4-bromophenol (1 g, 5.78 mmol) in DMF (10 ml) wereadded Intermediate 2 (1.49 g, 5.78 mmol) and K₂CO₃ (2.4 g, 17.34 mmol).The mixture was stirred at 100° C. for 4 h. Then the reaction mixturewas cooled to 25° C., washed with brine (30 mL) and extracted with EtOAc(10 mL×2). The combined organic layers were separated, dried andconcentrated under vacuum. The resulting crude residue was purified bychromatography over silica gel (eluting with PE:EA=5:1) to give thetitle compound.

Step B:2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)butan-2-ol

A mixture of the product from Step A (1.41 g, 5.44 mmol),bis(pinacolato)diboron (1.52 g, 5.98 mmol), Pd(dppf)Cl₂ (398 mg, 0.544mmol) and KOAc (1.07 g, 10.88 mmol) in dioxane (14 mL) was stirred at90-100° C. under N₂ for 18 h. Then the reaction mixture was filtered andconcentrated under vacuum. The resulting crude product was purified bychromatography over silica gel (eluting with PE:EA=5:1) to give compoundthe title compound.

Step C: (5aR,6S,6aS)-ethyl3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of Intermediate 5 (774 mg, 1.63 mmol), the product from Step B(500 mg, 1.63 mmol), Pd(dtbpf)Cl₂ (104 mg, 0.16 mmol) and K₃PO₄ (691 mg,3.26 mmol) in THF/H₂O (5/1 mL) was stirred at 100° C. under N₂ for 15min in a microwave. The reaction mixture was washed with brine (20 mL)and extracted with EtOAc (6 mL×3). The combined organic layers wereconcentrated under vacuum. The resulting crude product was purified bychromatography over silica gel (eluting with PE:EA=10:1) to give thetitle compound. MS (ESI) m/e (M+H⁺): 574.

Step D:(5aR,6S,6aS)-3-((4-fluoro-4′-(3-hydroxy-3-methylbutoxy)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a solution of the product from Step C (400 mg, 0.698 mmol) inEtOH/H₂O (6/1 mL) was added LiOH (293 mg, 6.98 mmol). The reactionmixture was stirred at 20-24° C. for 18 h. Then HCl (2 mol/L) was addedto the reaction to adjust the pH to 5, and the reaction mixture waswashed with brine (15 mL) and extracted with EtOAc (5 mL×3). Thecombined organic layers were concentrated under vacuum. The resultingresidue was purified by preparative HPLC on a GILSON 281 instrumentfitted with a Diamonsil (150×20 mm×5 um) column, using water andacetonitrile as the eluents. Mobile phase A: water (containing 0.1% TFA,v/v), mobile phase B: acetonitrile. Gradient: 49-79% B, 0-10 min; 100%B, 10.5-12.5 min; 5% B, 13-15 min] to give the title compound. ¹HNMR(400 MHz, MeOH) δ: 8.06 (s, 1H), 7.51 (d, J=10.2 Hz, 1H), 7.45 (d, J=7.0Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 2H), 6.74 (s, 1H),5.44 (s, 2H), 4.15 (t, J=6.8 Hz, 2H), 3.23 (d, J=6.3 Hz, 1H), 3.04 (d,J=18.4 Hz, 1H), 2.92 (d, J=5.5 Hz, 1H), 2.46-2.39 (m, 1H), 2.02-1.93 (m,3H), 1.27 (s, 6H), 1.14 (br. s., 1H). MS (ESI) m/e (M+H⁺): 546.

Examples 6 to 11 were prepared in a similar manner to Example 5 usingthe appropriate intermediates and commercially available startingmaterials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+ 6

563 (5aR,6S,6aS)-3-((3′,4- difluoro-4′-(3- hydroxy-3-methyl-butoxy)-6-(trifluoro- methyl)-[1,1′- biphenyl]-3-yl) methoxy)-5,5a,6,6a-tetrahydrocyclopropa [4,5]cyclopenta[1,2-c] pyridine-6-carboxylic 564acid 7

563 (5aR,6S,6aS)-3-((2′,4- difluoro-4′-(3-hydroxy- 3-methylbutoxy)-6-(trifluoro-methyl)- [1,1′-biphenyl]-3- yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa [4,5]cyclopenta[1,2-c] pyridine-6-carboxylic acid564 8

597 (5aR,6S,6aS)-3-((2′,4- difluoro-4′-(3-(methyl- sulfonyl)-propoxy)-6-(trifluoromethyl)-[1,1′- biphenyl]-3-yl)methoxy)- 5,5a,6,6a-tetrahydro-cyclopropa[4,5]cyclo- penta[1,2-c]pyridine- 6-carboxylic acid 598 9

595 (5aR,6S,6aS)-3- ((2′,4,6′-trifluoro-4′- (2-(3-hydroxy-oxetan-3-yl)ethoxy)- 6-(trifluoromethyl)- [1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a- tetrahydrocyclopropa [4,5]cyclopenta[1,2-c]pyridine-6-carboxylic acid 596 10

581 (5aR,6S,6aS)-3-((2′,4,6′- trifluoro-4′-(3-hydroxy-3-methylbutoxy)-6- (trifluoromethyl)-[1,1′- biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo- propa[4,5]cyclopenta [1,2-c]pyridine-6-carboxylic acid 582 11

545 (5aR,6S,6aS)-3-((6-(di- fluoro-methyl)-3',4-di-fluoro-4'-(3-hydroxy-3- methyl-butoxy)-[1,1'- biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro- cyclopropa[4,5]cyclo- penta[1,2-c]pyridine-6-carboxylic acid 546

Example 12(5aR,6S,6aS)-3-((4′-(4,4-difluoro-3-hydroxy-3-methylbutoxy)-4-fluoro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A:4-(4-bromophenoxy)-1,1-difluoro-2-methyl-1-(phenylsulfonyl)butan-2-ol

A mixture of Intermediate 4 (434.37 mg, 1 mmol, 4-bromophenol (138 mg,0.8 mmol) and K₂CO₃ (276 mg, 2.0 mmol) in DMF (10 mL) was stirred atroom temperature overnight. The resulting mixture was filtered and thefiltrate was partitioned between EtOAc and water. The aqueous phase wasseparated, washed with brine, dried over Na₂SO₄, filtered andconcentrated under vacuum. The resulting residue was purified bychromatography over silica gel (eluting with PE:EA=4:1) to give thetitle compound as a yellow oil. MS (ESI) m/e (M+H⁺): 463.0

Step B: 4-(4-bromophenoxy)-1,1-difluoro-2-methylbutan-2-ol

To a suspension of the product from Step A (300 mg, 0.69 mmol), NaOAc(1.3 g, 15.85 mmol) in AcOH/H₂O/DMF (2 mL/8 mL/20 mL) was added Mgpowder (251 mg, 10.34 mmol) and the mixture was stirred at roomtemperature overnight. The reaction mixture was then partitioned betweenEtOAc and water. The aqueous layer was separated, and extracted withEtOAc three times. The combined organic layers were washed with water,dried and concentrated in vacuo. The resulting crude product waspurified by chromatography over silica gel (eluting with PE:EA=5:1) toafford the title compound as a yellow oil. MS (ESI) m/e (M+H⁺): 295.1.

Step C:(5aR,6S,6aS)-ethyl3-((4′-(4,4-difluoro-3-hydroxy-3-methylbutoxy)-4-fluoro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of the product from Step B (30 mg, 0.102 mmol), Intermediate 6(63.6 mg, 0.122 mmol), K₃PO₄ (64.7 mg, 0.305 mmol) and Pd(dppf)Cl₂(13.25 mg, 0.020 mmol) in THF (3 ml) and water (1 ml) was heated in amicrowave at 100° C. for 30 min under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was filtered, theinsoluble part was removed. The filtrate was extracted with EtOAc. Theorganic layer was separated, washed with water, dried and concentratedto give the title compound as a brown oil, which was used in the nextstep without further purification. MS (ESI) m/e (M+H⁺): 609.2.

Step D:(5aR,6S,6aS)-3-((4′-(4,4-difluoro-3-hydroxy-3-methylbutoxy)-4-fluoro-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a mixture of the crude product from Step C (55 mg, crude) in MeOH(1.00 mL), THF (1.00 mL) and water (1.00 mL) was added lithium hydroxide(33 mg, 0.835 mmol), and the reaction mixture was stirred at roomtemperature for 2 hrs. The resulting mixture was acidified with HCl (2N) to pH=3, and extracted with ethyl acetate. The combined organiclayers were washed with water, brine, dried over Na₂SO₄ and concentratedin vacuo to afford a residue, which was purified by preparative HPLC ona GILSON 281 instrument fitted with a Waters XSELECT C18 (150×30 mm×5um) column using water and acetonitrile as the eluents. Mobile phase A:water (containing 0.1% TFA, v/v), mobile phase B: acetonitrile.Gradient: 55-75% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min] toprovide the title compound as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ:8.17 (s, 1H), 7.49-7.42 (m, 2H), 7.23 (d, J=8.5 Hz, 2H), 6.93 (d, J=8.5Hz, 2H), 6.70 (s, 1H), 5.69 (s, 1H), 5.46 (s, 2H), 4.27 (t, J=6.0 Hz,2H), 3.32 (br. s., 1H), 3.12-3.00 (m, 2H), 2.59-2.51 (m, 1H), 2.24-2.02(m, 2H), 1.36 (s, 3H), 1.26 (br. s., 1H). MS (ESI) m/e (M+H⁺): 581.2.

Example 13 was prepared in a similar manner to Example 12 using theappropriate intermediates and commercially available starting materials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+13

595 (5aR,6S,6aS)-3-((2'- (difluoromethyl)-4- fluoro-4'-(3-hydroxy-3-methyl-butoxy)-6- (trifluoromethyl)- [1,1'-biphenyl]-3-yl)-methoxy)-5,5a,6,6a- tetra-hydrocyclo- propa[4,5]cyclopenta[1,2-c]pyridine-6- carboxylic acid 596

Example 14(5aR,6S,6aS)-3-((4-fluoro-4′-(2-(3-hydroxyoxetan-3-yl)ethoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 3-(2-(4-bromo-3-methylphenoxy)ethyl)oxetan-3-ol

A mixture of intermediate 3 (200 mg, 0.734 mmol), 4-bromo-3-methylphenol(137 mg, 0.732 mmol) and K₂CO₃ (152 mg, 1.102 mmol) in acetonitrile (4ml) was stirred at 80° C. overnight. The reaction mixture was extractedwith EtOAc three times. The combined organic layers were washed withwater, dried and concentrated in vacuo to yield a residue, which waspurified by flash chromatography over silica gel (eluting withPE:EA=4:1) to afford the title compound as a yellow oil. MS (ESI) m/e(M+H⁺): 288.

Step B: (5aR,6S,6aS)-ethyl3-((4-fluoro-4′-(2-(3-hydroxyoxetan-3-yl)ethoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of the product from Step A (50 mg, 0.174 mmol), Intermediate 6(109 mg, 0.209 mmol), Pd(dtbpf)Cl₂ (11.35 mg, 0.017 mmol) and K₃PO₄trihydrate (93 mg, 0.348 mmol) in THF (3 mL) and water (1 mL) was heatedin a microwave at 100° C. for 30 min under a nitrogen atmosphere. Aftercooling to room temperature, the reaction mixture was filtered and thefiltrate was extracted with EtOAc. The combined organic layers werewashed with water, dried and concentrated in vacuo to give the titlecompound as a crude product, which was used in the next step withoutpurification. MS (ESI) m/e (M+H⁺): 602.

Step C:(5aR,6S,6aS)-3-((4-fluoro-4′-(2-(3-hydroxyoxetan-3-yl)ethoxy)-2′-methyl-6-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a mixture of the product from Step B (31 mg, 0.052 mmol) in MeOH(3.00 ml), THF (3.00 ml) and water (3.00 ml) was added lithium hydroxide(4.94 mg, 0.206 mmol), and the reaction was stirred at room temperaturefor 2 hrs. The resulting mixture was acidified with 2N HCl to pH=3 andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, dried over Na₂SO₄ and concentrated in vacuo to afforda residue, which was purified by preparative HPLC on a GILSON 281instrument fitted with a Phenomenex Gemini C18 (150×30 mm×5 um) column,using water and acetonitrile as the eluents. Mobile phase A: water(containing 0.1% TFA, v/v), mobile phase B: acetonitrile. Gradient:45-65% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min] to providethe title compound as a yellow solid. ¹H NMR (400 MHz, MeOH-d₄) δ: 8.05(br. s., 1H), 7.54 (d, J=9.4 Hz, 1H), 7.33 (t, J=5.7 Hz, 1H), 6.96 (d,J=6.7 Hz, 1H), 6.83-6.60 (m, 3H), 5.46 (br. s., 2H), 4.71 (d, J=6.3 Hz,2H), 4.62 (d, J=6.7 Hz, 2H), 4.18 (br. s., 2H), 3.24 (d, J=18.8 Hz, 1H),3.03 (d, J=17.6 Hz, 1H), 2.91 (br. s., 1H), 2.43 (br. s., 1H), 2.30 (t,J=5.7 Hz, 2H), 2.00 (d, J=8.6 Hz, 1H), 1.89 (br. s., 3H), 1.13 (br. s.,1H). MS (ESI) m/e (M+H⁺): 574.

Example 15(5aR,6S,6aS)-3-((2-fluoro-5-(5-fluoro-6-(3-hydroxy-3-methylbutoxy)pyridin-3-yl)-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 5-bromo-3-fluoropyridin-2-ol

A mixture of 5-bromo-3-fluoro-2-methoxypyridine (1.2 g, 5.82 mmol) inconcentrated HCl (5 ml, 60.9 mmol) was stirred at 100° C. for 12 h. Thenthe mixture was concentrated in vacuo to give the title compound as awhite solid. MS (ESI) m/e (M+H⁺): 192, 194.

Step B: 4-((5-bromo-3-fluoropyridin-2-yl)oxy)-2-methylbutan-2-ol

To a mixture of Intermediate 2 (740 mg, 2.86 mmol) and the product fromStep A (500 mg, 2.60 mmol) in DMF (4 mL) was added K₂CO₃ (720 mg, 5.21mmol). The resulting reaction mixture was stirred at 80° C. for 3 h, andthen filtered. The filtrate was concentrated and the resulting residuewas purified by chromatography over silica gel (eluting with PE:EA=1:1),to give the title compound. MS (ESI) m/e (M+H⁺): 278, 280.

Step C:(5aR,6S,6aS)-3-((2-fluoro-5-(5-fluoro-6-(3-hydroxy-3-methylbutoxy)pyridin-3-yl)-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a solution of the product from Step B (30 mg, 0.108 mmol) in THF (2.0mL) was added Intermediate 6 (45 mg, 0.086 mmol), K₃PO₃/H₂O (0.5 ml, 1mol/L) and Pd(dtbpf)Cl₂ (8 mg, 0.01 mmol). The resulting mixture washeated at 100° C. in a microwave for 15 min. Then the reaction mixturewas purified by chromatography over silica gel (eluting with PE:EA=3:1)to give the title compound. MS (ESI) m/e (M+H⁺): 593.

Step D:(5aR,6S,6aS)-3-((2-fluoro-5-(5-fluoro-6-(3-hydroxy-3-methylbutoxy)pyridin-3-yl)-4-(trifluoromethyl)benzyl)oxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a solution of the product from Step C (16 mg, 0.027 mmol) in MeOH (3mL) and water (1 mL) was added LiOH (50 mg, 2 mmol). The resultingmixture was stirred at rt. for 2 hours. Then water was added and thesolution was acidified with HCl (1M) to pH=2.5, and extracted with EtOAc(10 mL×3). The combined organic layers were washed with brine, dried andconcentrated in vacuo to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ: 7.33 (d, J=10.0 Hz, 1H), 6.65 (s, 1H), 5.53-5.44 (m, 2H), 4.63(t, J=7.0 Hz, 2H), 3.23 (d, J=6.0 Hz, 1H), 3.09-2.95 (m, 2H), 2.53 (dt,J=3.5, 6.3 Hz, 1H), 2.07 (t, J=7.0 Hz, 2H), 1.35 (s, 6H), 1.26 (s, 1H).MS (ESI) m/e (M+H⁺): 565.

Examples 16 and 17 were prepared in a similar manner to Example 15 usingthe appropriate intermediates and commercially available startingmaterials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+16

595 (5aR,6S,6aS)-3-((5- (6-(4,4-difluoro-3- hydroxy-3-methyl-butoxy)-2-methyl- pyridin-3-yl)-2- fluoro-4-(trifluoro- methyl)-benzyl)-oxy)-5,5a,6,6a- tetrahydro-cyclo- propa[4,5]cyclopenta[1,2-c]pyridine-6- carboxylic acid 597 17

560 (5aR,6S,6aR)-3-((5- (6-(4,4-difluoro-3- hydroxy-3-methyl-butoxy)-2,4-di- methylpyridin-3-yl)- 2,4-difluorobenzyl)oxy)-5,5a,6,6a-tetra- hydrocyclopropa[4,5] cyclopenta[1,2-c]pyridine-6-carboxylic acid 561

Example 18

(5aR,6S,6aS)-3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocycloprop[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 2-bromo-1,3-dimethyl-5-((4-methylpent-3-en-1-yl)oxy)benzene

A mixture of 5-bromo-2-methylpent-2-ene (500 mg, 3.07 mmol),4-bromo-3,5-dimethylphenol (617 mg, 3.07 mmol), K₂CO₃ (848 mg, 6.13mmol) and acetone (10 mL) was stirred at 60° C. for 18 hours. Then thereaction was cooled to rt and poured into water (30 mL), and theresulting mixture was extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and the solvent wasevaporated under reduced pressure. The resulting residue was purified bychromatography over silica gel (eluting with PE:EA=100:1 to 50:1) togive the title compound.

Step B: 5-(4-bromo-3,5-dimethylphenoxy)-2-methylpentane-2,3-diol

To a mixture of2-bromo-1,3-dimethyl-5-((4-methylpent-3-en-1-yl)oxy)benzene (600 mg,2.12 mmol) and 4-methylmorpholine 4-oxide (745 mg, 6.36 mmol) in aco-solvent of acetone and water (22 mL, 10:1) was added osmium(VIII)oxide (26.9 mg, 0.106 mmol) at room temperature. The resulting mixturewas stirred at room temperature for 12 hrs, then quenched by theaddition of solid Na₂SO₃ (1.0 g). The resulting mixture was stirred for1.5 hrs at room temperature, then diluted with DCM and washed withwater, followed by saturated NaHCO₃ solution, water, and brine. Theseparated organic layer was then dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified bychromatography over silica gel (eluting with PE:EA=1:1) to give thetitle compound. MS (ESI) m/e (M+H⁺): 317.1/319.1.

Step C: (5aR,6S,6aS)-tert-butyl3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of PdCl₂(dppf) (27.7 mg, 0.038 mmol), K₂CO₃ (131 mg, 0.946mmol), intermediate 11 (208 mg, 0.416 mmol), and 5-(4-bromo-3,5-dimethylphenoxy)-2-methylpentane-2,3-diol (120 mg, 0.378 mmol) in a co-solventof THF (2.0 mL) and water (0.7 mL) was charged in a sealed tube under N₂atmosphere, and then radiated by microwave at 100° C. for 30 mins. Aftercooling to room temperature, the mixture was filtered. The filtrate wasdiluted with DCM (25 mL) and washed with water (20 mL), dried overNa₂SO₄ and filtered, concentrated in vacuo to give the crude product,which was purified by chromatography over silica gel (eluting withPE:EA=2:1) to give the title compound. MS (ESI) m/e (M+H⁺): 610.3.

Step D: (5aR,6S,6aS)-tert-butyl3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]-cyclopenta[1,2-c]pyridine-6-carboxylate

(5aR,6S,6aS)-tert-butyl3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(180 mg, 0.295 mmol) was resolved by SFC (Column: Chiralcel OD-H 250×4 6mm I.D., 5 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40%Flow rate: 2.35 mL/min Wavelength: 220 nm) to afford the first peakisomer with shorter retention time in chiral HPLC(5aR,6S,6aS)-tert-butyl3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate;and the second peak isomer with longer retention time in chiral HPLC(5aR,6S,6aS)-tert-butyl3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6.MS (ESI) m/e (M+H⁺): 610.3 for both.

Step E:(5aR,6S,6aS)-3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

To a mixture of (5aR,6S,6aS)-tert-butyl 3-((4′-((3,4-dihydroxy-4-methylpentyl)oxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(first peak isomer, 75 mg, 0.123 mmol) in a co-solvent of THF (2 ml),MeOH (2 mL) and H₂O (2 mL) was added NaOH (24.60 mg, 0.615 mmol) and theresulting mixture was stirred at 60° C. for 2 hrs. Then the resultingmixture was cooled to rt, acidified by HCl (2 N) to pH=6, and thenextracted with EtOAc. The organic layer was separated, washed with water(20 mL) and brine, dried over Na₂SO₄ and concentrated in vacuo to getthe crude product, which was purified by silica gel preparative TLC(PE/EA=1:1) to give the title compound. ¹H NMR (400 MHz, MeOD-d₄) δ:7.97-8.09 (m, 1H), 7.16-7.27 (m, 1H), 6.97-7.09 (m, 1H), 6.66 (s, 2H),6.63 (s, 1H), 5.33 (s, 2H), 4.07-4.17 (m, 2H), 3.51-3.59 (m, 1H),3.14-3.25 (m, 1H), 2.94-3.04 (m, 1H), 2.85-2.91 (m, 1H), 2.34-2.45 (m,1H), 2.03-2.17 (m, 1H), 1.91 (s, 6H), 1.62-1.75 (m, 1H), 1.18 (d,J=10.96 Hz, 6H), 1.06-1.13 (m, 1H). MS (ESI) m/e (M+H⁺): 554.2.

Examples 19 to 21 were prepared in a similar manner to Example 18 usingthe appropriate intermediates and commercially available startingmaterials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+19

539 (5aR,6S,6aS)-3-((4′- (3,4-dihydroxy-3- methyl-butoxy)-4,6-difluoro-2′,6′- dimethyl-[1,1′- biphenyl]-3-yl) methoxy)-5,5a,6,6a-tetrahydro- cyclopropa[4,5]- cyclopenta[1,2-c] pyridine-6-carboxylicacid 540 20

576 (5aR,6S,6aS)-3-((5- (6-(3,4-dihydroxy- 3-methyl-butoxy)-2-methylpyridin-3-yl)- 2-fluoro-4-(tri-fluoro- methyl)benzyl)-oxy)-5,5a,6,6a-tetra-hydro- cyclopropa[4,5]- cyclopenta[1,2-c]-pyridine-6-carboxylic acid 577 21

545 (5aR,6S,6aS)-3-((2′- chloro-4′-((S)-3,4- dihydroxy-3-methyl-butoxy)-4,6- di-fluoro-[1,1′- biphenyl]-3-yl) methoxy)-5,5a,6,6a-tetrahydrocyclopropa [4,5]cyclopenta[1,2-c] pyridine-6-carboxylic acid546

Example 22

(5aR,6S,6aS)-3-((4,6-difluoro-4′-(3-hydroxy-2-(2-hydroxypropan-2-yl)-3-methylbutoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: 3-methylbut-2-en-1-yl benzoate

Benzoyl chloride (9.71 mL, 84 mmol) was added to a stirred, cooledmixture of 3-methylbut-2-en-1-ol (6 g, 69.7 mmol) in pyridine (30 ml) at0° C. and the mixture was stirred at 20° C. for 16 hours. Then themixture was quenched with water, and extracted with EtOAc. The combinedorganic layer was washed with 2 N aqueous HCl, dried over anhydrousNa₂SO₄, filtered, and the filtrate was concentrated in vacuo to give thecrude product. The resulting residue was purified by chromatography oversilica gel (eluting with PE) to give the title compound.

Step B: (3,3-dimethyloxiran-2-yl)methyl benzoate

m-CPBA (7.65 g, 35.5 mmol) was added to a stirred, cooled mixture of3-methylbut-2-en-1-yl benzoate (5 g, 23.65 mmol) in DCM (100 mL) at 0°C., and the mixture was stirred at 20° C. for 16 hours. Then the mixturewas quenched with water and extracted with DCM. The combined organiclayers were washed with saturated Na₂S₂O₃, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo to give the crudeproduct, which was purified by chromatography over silica gel (elutingwith PE:EA=20:1 to 10:1) to provide the title compound.

Step C: 3-methyl-2-(prop-1-en-2-yl)butane-1,3-diol

Prop-1-en-2-ylmagnesium bromide (38.8 ml, 19.40 mmol, 0.5 M in THF) wasadded to a stirred, cooled mixture of copper(I) bromide-dimethyl sulfide(997 mg, 4.85 mmol) and dimethylsulfane (0.7 ml, 9.53 mmol) in Et₂O (10mL) at −25° C., then a solution of (3,3-dimethyloxiran-2-yl)methylbenzoate (500 mg, 2.424 mmol) in Et₂O (5 mL) was added dropwise. Theresulting mixture was stirred at −25° C. for 5 hours then allowed towarm to 20° C. and stirred for 16 hours. The mixture was poured intosaturated NH₄Cl/NaOH(pH=8) at 0° C., and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, and filtered. The filtrate was concentrated in vacuo to give thecrude product which was purified by chromatography over silica gel(eluting with PE:EA=10:1 to 1:1) to give the title compound.

Step D: 2-(2-hydroxypropan-2-yl)-3-methylbut-3-en-1-yl4-methylbenzenesulfonate

4-Methylbenzene-1-sulfonyl chloride (436 mg, 2.288 mmol) was added to astirred, cooled mixture of 3-methyl-2-(prop-1-en-2-yl)butane-1,3-diol(300 mg, 2.080 mmol), triethylamine (0.870 ml, 6.24 mmol) and DMAP (50.8mg, 0.416 mmol) in DCM (20 ml) at 0° C., and the resulting mixture wasstirred at 20° C. for 16 hours. The mixture was quenched with water, andextracted with DCM. Then the combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo. The resulting residue was purified bychromatography over silica gel (eluting with PE:EA=10:1 to 2:1) to givethe title compound.

Step E:3-((4-bromo-3,5-dimethylphenoxy)methyl)-2,4-dimethylpent-4-en-2-ol

A mixture of 2-(2-hydroxypropan-2-yl)-3-methylbut-3-en-1-yl4-methylbenzenesulfonate (356 mg, 1.194 mmol),4-bromo-3,5-dimethylphenol (200 mg, 0.995 mmol) and Cs₂CO₃ (648 mg,1.989 mmol) in NMP (5 mL) was stirred at 100° C. for 16 hours undernitrogen. After cooling to room temperature, the mixture was dilutedwith EtOAc. The organic layer was separated, and washed with water. Thewater layer was separated and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound, which was used inthe next step without further purification.

Step F:4-(4-bromo-3,5-dimethylphenoxy)-2-methyl-3-(2-methyloxiran-2-yl)butan-2-ol

m-CPBA (222 mg, 1.029 mmol) was added to a stirred, cooled mixture of3-((4-bromo-3,5-dimethylphenoxy)methyl)-2,4-dimethylpent-4-en-2-ol (374mg, 0.686 mmol) in DCM (5 mL) at 0° C. and the mixture was stirred at20° C. for 16 hours. The mixture was then quenched with water, andextracted with DCM. The combined organic layers were washed withsaturated Na₂S₂O₃, dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to give the title compound, which wasused in the next step without further purification.

Step G:3-((4-bromo-3,5-dimethylphenoxy)methyl)-2,4-dimethylpentane-2,4-diol

LiAlH₄ (39.2 mg, 1.032 mmol) was added to a stirred, cooled mixture of4-(4-bromo-3,5-dimethylphenoxy)-2-methyl-3-(2-methyloxiran-2-yl)butan-2-ol(253 mg, 0.516 mmol) in THF (5 mL) at 0° C. and the mixture was stirredat 20° C. for 16 hours. Then the mixture was quenched with water (0.2mL), NaOH (15%) (0.2 mL) and water (0.6 mL) again, and stirred for 15minutes. The resulting mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue, which was purified bychromatography over silica gel (eluting with PE:EA=2:1) to afford thetitle compound.

Step H: (5aR,6S,6aS)-tert-butyl3-((4,6-difluoro-4′-(3-hydroxy-2-(2-hydroxypropan-2-yl)-3-methylbutoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

A mixture of3-((4-bromo-3,5-dimethylphenoxy)methyl)-2,4-dimethylpentane-2,4-diol(100 mg, 0.290 mmol), intermediate 11 (145 mg, 0.290 mmol), K₂CO₃ (80mg, 0.579 mmol) and Pd(dtbpf)Cl₂ (18.88 mg, 0.029 mmol) in THF (2 ml)and water (0.5 ml) was charged in a sealed tube and heated at 100° C.with microwave irradation for 30 mins under N₂ protection. After coolingto room temperature, the mixture was filtered through Celite™, andrinsed with EtOAc. The organic layer was washed with water, and thewater layer was extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to give a residue, which was purifiedvia silica gel preparative TLC (eluting with PE:EA=3:1) to give thetitle compound. MS (ESI) m/e (M+H⁺): 638.2.

Step I:(5aR,6S,6aS)-3-((4,6-difluoro-4′-(3-hydroxy-2-(2-hydroxypropan-2-yl)-3-methylbutoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydro-cyclopropa-[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

A mixture of (5aR,6S,6aS)-tert-butyl3-((4,6-difluoro-4′-(3-hydroxy-2-(2-hydroxypropan-2-yl)-3-methylbutoxy)-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(63 mg, 0.099 mmol) and LiOH.H₂O (124 mg, 2.96 mmol) in THF (4 ml), MeOH(1 ml) and water (1 ml) was stirred at 50° C. for 16 hours. Aftercooling to room temperature, the mixture was acidified with 2N HCl topH=3, and then extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and filtered. Thefiltrate solvent was evaporated under reduced pressure to give aresidue, which was purified by reverse preparative HPLC (preparativeHPLC on a GILSON 281 instrument fitted with a Diamonsil 150*20 mm*Sumusing water and acetonitrile as the eluents. Mobile phase A: water(containing 0.1% TFA, v/v), mobile phase B: acetonitrile. Gradient:48-78% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min) to give thetitle compound. ¹H NMR (400 MHz, MeOD-d₄) δ: 8.08 (s, 1H), 7.26 (t,J=8.22 Hz, 1H), 7.07 (t, J=9.68 Hz, 1H), 6.83 (s, 1H), 6.67 (s, 2H),5.38 (s, 2H), 3.99 (d, J=4.30 Hz, 2H), 3.25 (br. s., 1H), 3.08 (d,J=18.98 Hz, 1H), 2.94 (d, J=4.89 Hz, 1H), 2.43-2.47 (m, 1H), 2.08 (t,J=4.11 Hz, 1H), 1.93 (s, 6H), 1.42 (s, 6H), 1.33 (s, 6H), 1.16 (br. s.,1H). MS (ESI) m/e (M+H⁺): 582.2.

Example 23(5aR,6S,6aS)-3-((4′-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

Step A: (4-bromo-3, 5-dimethylphenyl) methanol

NaBH₄ (0.710 g, 18.77 mmol) was added to a stirred, cooled mixture of4-bromo-3,5-dimethyl-benzaldehyde (2 g, 9.39 mmol) in MeOH (20 mL) at 0°C. Then the mixture was allowed to warm to rt and stirred for 2 h. Themixture was quenched by adding 1N HCl dropwise until the mixture pH=7,and then extracted with DCM. The organic layer was separated, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound, which was used in the next step without further purification.

Step B: 2-bromo-5-(bromomethyl)-1,3-dimethylbenzene

Phosphorous tribromide (0.539 ml, 5.72 mmol) was added to a stirred,mixture of (4-bromo-3, 5-dimethylphenyl) methanol (2.05 g, 9.53 mmol) inDCM (20 mL) at 0° C., and the mixture was allowed to warm to rt andstirred for 2 h. Then water (50 mL) was added to the mixture at 0° C.,and the mixture was extracted with DCM. The organic layer was separated,washed with brine, dried with anhydrous Na₂SO₄, and filtered. Thefiltrate solvent was concentrated in vacuo to give the title compound,which was used in the next step without further purification.

Step C: 4-(4-bromo-3,5-dimethylphenyl)butan-2-one

A mixture of 2-bromo-5-(bromomethyl)-1,3-dimethylbenzene (2.45 g, 8.81mmol), pentane-2,4-dione (0.882 g, 8.81 mmol) and K₂CO₃ (1.218 g, 8.81mmol) in MeOH (25 ml) was stirred at 80° C. for 16 h. Then the mixturewas concentrated in vacuo, and diluted with water and EtOAc. The aqueouslayer was separated and extracted with EtOAc. The combined organiclayers were washed with brine, dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue, which was purified via silicagel chromatography (eluting with PE to PE:EA=92:8) to give the titlecompound.

Step D: 2-bromo-1,3-dimethyl-5-(3-methylbut-3-en-1-yl)benzene

To a mixture of PPh₃CH₃Br (3.36 g, 9.41 mmol) in THF (15 mL) was addeddropwise t-BuOK (8.82 ml, 8.82 mmol), followed by the dropwise additionof 4-(4-bromo-3,5-dimethylphenyl)-butan-2-one (1.5 g, 5.88 mmol) in THF(5 mL) The reaction mixture was stirred at 20° C. for 15 h, thenconcentrated in vacuo and diluted with water and EtOAc. The aqueouslayer was separated and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (eluting with PE to PE:EA=95:5) to give the titlecompound.

Step E: 4-(4-bromo-3,5-dimethylphenyl)-2-methylbutane-1,2-diol

To a mixture of 2-bromo-1,3-dimethyl-5-(3-methylbut-3-en-1-yl)benzene(1.0 g, 3.95 mmol) and N-methylmorpholine N-oxide (1.388 g, 11.85 mmol)in acetone (15 ml) and water (1.5 ml) was added OsO₄ (0.100 g, 0.395mmol) and the resulting mixture was stirred at 22° C. for 18 h. Then themixture was quenched by adding Na₂S₂O₃ and stirred for 1 h. Theresulting mixture was diluted with water and EtOAc. The aqueous layerwas separated, extracted with EtOAc, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound, which wasused in the next step without further purification.

Step F: (5aR,6S,6aS)-tert-butyl3-((4′-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To a mixture of 4-(4-bromo-3,5-dimethylphenyl)-2-methylbutane-1,2-diol(200 mg, 0.696 mmol), intermediate 11 (383 mg, 0.766 mmol), K₂CO₃ (289mg, 2.089 mmol) in THF (3 ml) and water (1 ml) was added Pd(dtbpf)Cl₂(45.4 mg, 0.070 mmol). The resulting mixture was sealed in a 10 mLvial/autoclave and stirred at 100° C. for 0.5 h under N₂ protection.After cooling to room temperature, the mixture was filtered overCelite′, and then diluted with EtOAc and water. The aqueous layer wasseparated and extracted with EOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified by prep-HPLCto give the title compound. MS (ESI) m/e (M+H⁺): 580.2.

Step G:(5aR,6S,6aS)-3-((4′-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylicacid

LiOH.H₂O (213 mg, 5.07 mmol) was added to a stirred, solution of(5aR,6S,6aS)-tert-butyl3-((4′-(3,4-dihydroxy-3-methylbutyl)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(245 mg, 0.423 mmol) in water (0.5 mL), THF (0.5 mL) and MeOH (2 mL) Thereaction was stirred at 50° C. for 13 h, then the reaction was cooledand acidified with 1N HCl to pH=3. Then the reaction mixture wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The resulting residue was purified via silica gel preparative TLC(eluting with ethyl acetate) to afford the title compound. ¹H NMR (400MHz, CD₃OD-d₄) δ: 8.04 (s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.05 (t, J=9.6Hz, 1H), 6.95 (s, 2H), 6.67 (s, 1H), 5.35 (s, 2H), 3.41 (s, 2H),3.26-3.17 (m, 1H), 3.07-2.98 (m, 1H), 2.90 (d, J=5.2 Hz, 1H), 2.65-2.59(m, 2H), 2.46-2.38 (m, 1H), 1.92 (s, 6H), 1.82-1.68 (m, 2H), 1.20 (s,3H), 1.11 (br. s., 1H). MS (ESI) m/e (M+H⁺): 524.2.

Example 24 Sodium(5aR,6S,6aS)-3-((4′-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

Step A: (S)-4-(2-(4-bromo-3, 5-dimethylphenoxy)ethyl)-2, 2-dimethyl-1,3-dioxolane

To a solution of 4-bromo-3,5-dimethylphenol (15 g, 74.6 mmol),(4S)-(+)-4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (14.18 g, 97mmol) and tris-N-butylphosphine (24.22 ml, 97 mmol) in THF (200 ml) at0° C. was added DIAD (18.86 ml, 97 mmol). The reaction mixture waswarmed to room temperature and stirred overnight for 3 days. Then themixture was concentrated in vacuo and the resulting residue was purifiedvia silica gel chromatography (eluting with hexanes to hexanes:ethylacetate=75:25) to provide the title compound.

Step B: (S)-4-(4-bromo-3,5-dimethylphenoxy)butane-1,2-diol

To a solution of(S)-4-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)-2,2-dimethyl-1,3-dioxolane(8.1 g, 24.60 mmol) in MeOH (700 ml) and water (30 ml) at roomtemperature was added hydrochlorid acid (4M in Dioxane, 7.38 ml, 29.5mmol). The reaction mixture was stirred overnight, then concentrated invacuo. The resulting mixture was neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to provide the title compound, which was useddirectly in the next step. MS (ESI) m/e (M+H⁺): 289.2.

Step C: (5aR,6S,6aS)-tert-butyl3-((4′-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To a mixture of X-Phos Second Generation Precatalyst (473 mg, 0.601mmol), intermediate 11 (3.1 g, 6.21 mmol) and(S)-4-(4-bromo-3,5-dimethylphenoxy)butane-1,2-diol (2.154 g, 7.45 mmol)under N₂ was added degassed THF (60 ml) and K₃PO₄ (18.62 ml, 18.62mmol). The reaction was then stirred at 40° C. for 45 min, and stirredovernight at room temperature. Then the reaction was diluted with EtOAc,washed with water, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The resulting residue was purified bychromatography over silica gel (eluting with hexanes to ethyl acetate)to give the title compound. MS (ESI) m/e (M+H⁺): 581.6.

Step D: Sodium(5aR,6S,6aS)-3-((4′-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate

To a solution of (5aR,6S,6aS)-tert-butyl3-((4′-((S)-3,4-dihydroxybutoxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′-biphenyl]-3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-c]pyridine-6-carboxylate(3.57 g, 6.14 mmol) in THF (60 ml) and MeOH (60 ml) at room temperaturewas added 10 N NaOH (1.841 ml, 18.41 mmol). The mixture was warmed to40° C. and stirred for 3 h, and then stirred at rt overnight. Then NaOH(10 N, 0.4 ml) was added and the reaction was stirred at rt overnight.The mixture was then quenched at room temperature with 1N HCl andextracted with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified via silica gel column (120 g, elutingwith 0-20% MeOH in DCM) to give the title compound as the acid. To asolution of crude title compound in acetonitrile (40 ml) at roomtemperature was added NaOH (3.81 ml, 3.81 mmol) and the mixture waslyophilized to give the title compound as the sodium salt. (¹HNMR (500MHz, CD3OD) δ: 7.98 (S, 1H), 7.23 (t, 1H, J=8.3 Hz), 7.08 (t, 1H, J=9.3Hz), 6.69 (s, 2H), 6.64 (s, 1H), 5.34 (s, 2H), 4.12 (broad multiplet,2H), 3.88 (broad multiplet, 1H), 3.54 (m, 2H0, 3.18 (dd, 1H, J₁₃=18.6Hz, J₁₂=6.4 Hz), 2.98 (s, 1H), 2.75 (d, 1H, J=4.9 Hz), 2.30 (s, 1H),1.94 (s, 6H), 1.81 (1H). (m/z): 525.5 (M+H).

Examples 25 and 26 were prepared in a similar manner to Example 24 usingthe appropriate intermediates and commercially available startingmaterials.

LC/MS Ex- (ESI) am- observed ple Structure M.W. Compound Name [M + 1]+25

524 (5aR,6S,6aS)-3-((4′- ((R)-3,4-dihydroxy- butoxy)-4,6-difluoro-2′,6′-dimethyl-[1,1′- biphenyl]-3-yl) methoxy)-5,5a,6,6a-tetrahydrocyclo- propa[4,5]cyclopenta [1,2-c]pyridine-6- carboxylic acid525 26

545 (5aR,6S,6aS)-3-((6- chloro-4′-((R)-3,4- dihydroxybutoxy)-4,5,-difluoro-2′- methyl-[1,1′-biphenyl]- 3-yl)methoxy)-5,5a,6,6a-tetrahydrocyclo- propa[4,5]cyclopenta [1,2-c]pyridine-6- carboxylicacid 546

BIOLOGICAL ASSAYS Generation of GPR40-Expressing Cells:

Human and mouse GPR40 stable cell-lines were generated in CHO cellsstably expressing NFAT BLA (Beta-lactamase). A human GPR40 stablecell-line was generated in HEK cells stably expressing the aequorinexpressing reporter. The expression plasmids were transfected usinglipofectamine (Life Technologies) following manufacturer's instructions.Stable cell-lines were generated following drug selection.

FLIPR Assays:

FLIPR (Fluorimetric Imaging Plate Reader, Molecular Devices) assays wereperformed to measure agonist-induced calcium mobilization of the stableclones. For the FLIPR assay, one day before assay, GPR40/CHO NFAT BLAcells were seeded into black-wall-clear-bottom 384-well plates (Costar)at 1.4×10e4 cells/20 μL medium/well. The cells were incubated with 20μl/well of the assay buffer (HBSS, 0.1% BSA, 20 mM HEPES, 2.5 mMprobenecid, pH 7.4) containing 8 μM fluo-4, AM, 0.08% pluronic acid atroom temperature for 100 minutes. Fluorescence output was measured usingFLIPR. Compounds were dissolved in DMSO and diluted to desiredconcentrations with assay buffer. 13.3 μL/well of compound solution wasadded.

The compounds of the present invention, including the compounds inExamples 1-16, have EC₅₀ values less than 100 nanomolar (nM) in theFLIPR assay described above. The compounds in Examples 1-16 have theEC₅₀ values in the FLIPR assay listed in Table I.

Inositol Phosphate Turnover Assay 1:

The assay was performed in 96-well format. HEK cells stably expressinghuman GPR40 were plated to be 60-80% confluent within 72 h. After 72 h,the plates were aspirated and the cells washed with inositol-free DMEM(ICN). The wash media was replaced with 150 μL of 3H-inositol labelingmedia (inositol-free media containing 0.4% human albumin or 0.4% mousealbumin, 1× pen/strep antibiotics, glutamine, 25 mM HEPES to which wasadded 3H-myo-inositol NEN #NET114A 1 mCi/mL, 25 Ci/mmol diluted 1:150 inloading media with a final specific radioactivity of 1 μCi/150 μL).Alternatively, the human and mouse albumin can be added after theovernight labeling step before the addition of LiCl.

The assay was typically run the next day after 18 h labeling. On the dayof the assay, 5 μL of 300 mM LiCl was added to all wells and incubatedat 37 degrees for 20 min 0.75 μL of 200× compounds were added andincubated with the cells for 60 min at 37 degrees. The media was thenaspirated off and the assay terminated with the addition of 60 μL 10 mMformic acid. The cells were lysed for 60 min at room temperature. 15-30μL of lysate was mixed with 70 μL/1 mg YSi SPA beads (Amersham) in clearbottom Isoplates. The plates were shaken for 2 h at room temperature.Beads were allowed to settle and the plates were counted in the WallacMicrobeta.

The compounds of the present invention, including the compounds inExamples 1-16, 18, 24 and 25 have EC₅₀ values less than 3000 nanomolar(nM) in the Inositol Phosphate Turnover (IP1) Assay 1 described above.The compounds in Examples 1-16, 18, 24 and 25 have the EC₅₀ values inthe Inositol Phosphate Turnover (IP1) Assay 1 listed in Table I.

Inositol Phosphate Turnover (IP1) Assay 2:

The assay was performed in 384-well format. HEK cells stably expressinghuman GPR40 were plated at 15,000 cells per well in growth medium(DMEM/10% fetal calf serum). Cell plates were then incubated 16 hours at37 degrees in a 5% CO₂ incubator.

Measurement of Inositol Phosphate Turnover (IP1) was performed using theCisBio IP-One kit (Part number 62IPAPEB). After the 16 hour incubation,the cells were washed with HEPES buffer and 10 ul of stimulation buffer(prepared as described in the kit) was added to each well. In a separateplate, compounds were diluted in DMSO (400-fold over the finalconcentration in the assay well) and 25 nl was acoustically transferredto the appropriate well in the assay cell plate. The plates were thenincubated for 60 minutes at 37 degrees. 10 ul of detection buffer (alsoprepared as described in the IP-One kit) was added to each well and theplates were incubated for 60 minutes in the dark. The plates were thenread in a Perkin Elmer EnVision or equivalent reader able to measureFRET. Fluorescent ratio of emission at 665 and 620 nm was then convertedto IP1 concentration by back calculating from an IP1 standard curveprepared at the time of the assay.

The compounds of the present invention, including the compounds inExamples 17 and 19-26, have EC₅₀ values less than 3000 nanomolar (nM) inthe Inositol Phosphate Turnover (IP1) Assay 2 described above. Thecompounds in Examples 17 and 19-26 have the EC₅₀ values in the InositolPhosphate Turnover (IP1) Assay 2 listed in Table I.

In Vivo Studies:

Male C57BL/6N mice (7-12 weeks of age) are housed 10 per cage and givenaccess to normal diet rodent chow and water ad libitum. Mice arerandomly assigned to treatment groups and fasted 4 to 6 h. Baselineblood glucose concentrations are determined by glucometer from tail nickblood. Animals are then treated orally with vehicle (0.25%methylcellulose) or test compound. Blood glucose concentration ismeasured at a set time point after treatment (t=0 min) and mice are thenintraperitoneally-challenged with dextrose (2 g/kg). One group ofvehicle-treated mice is challenged with saline as a negative control.Blood glucose levels are determined from tail bleeds taken at 20, 40, 60min after dextrose challenge. The blood glucose excursion profile fromt=0 to t=60 min is used to integrate an area under the curve (AUC) foreach treatment. Percent inhibition values for each treatment aregenerated from the AUC data normalized to the saline-challengedcontrols.

TABLE I. EC₅₀ values (nM) for Examples in Human GPR40 FLIPR and IP1Assays

Example Human GPR40, Human GPR40 IP1, Human GPR40 IP1 Number FLIPR,EC₅₀, nM Assay 1, EC₅₀, nM Assay 2, EC₅₀, nM 1 16.75 9.889 ND 2 5.7462.981 ND 3 1.524 4.949 ND 4 14.38 5.245 ND 5 24.93 6.243 ND 6 10.8914.75 ND 7 11.23 11.39 ND 8 9.202 6.54 ND 9 6.894 11.12 ND 10 6.40427.22 ND 11 16.66 17.61 ND 12 12.46 20.34 ND 13 9.658 5.941 ND 14 10.375.538 ND 15 4.884 7.966 ND 16 ND 10.4 ND 17 ND ND 2.1 18 ND 19.2 ND 19ND ND 1.6 20 ND ND 3.1 21 ND ND 2.2 22 ND ND 3.1 23 ND ND 5.2 24 ND 4.61.3 25 ND 4.7 3.8 26 ND ND 0.7 ND is not determined

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

The scope of the claims should not be limited by the preferredembodiments set forth in the examples, but should be given the broadestinterpretation consistent with the description as a whole.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of the invention indicated above. The specific pharmacologicalresponses observed may vary according to and depending upon theparticular active compounds selected or whether there are presentpharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or differences inthe results are contemplated in accordance with the objects andpractices of the present invention.

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein A is phenyl; B isselected from the group consisting of: (1) phenyl, and (2) pyridyl; R¹is selected from the group consisting of: (1) halogen, (2) —CN, (3)—C₁₋₆alkyl, (4) —(CH₂)_(r)—OC₁₋₆alkyl, (5) —(CH₂)_(r)—C₃₋₆cycloalkyl,and (6) —(CH₂)_(r)—O—(CH₂)_(r)—C₃₋₆cycloalkyl, wherein each CH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to four substituents selected from halogen,—C₁₋₆alkyl and —(CH₂)_(v)—C₃₋₆cycloalkyl; R² is halogen; R³ when presentis selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl,and (3) —(CH₂)_(u)—C₃₋₆cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from halogen; R⁴ is selected from: (1)—OC₁₋₆alkyl, and (2) —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with one, two, three or four substituents selected from R⁵;R⁵ is selected from the group consisting of: (1) —(CH₂)_(s)halogen, (2)—C₁₋₆alkyl, (3) —(CH₂)_(s)—O—C₁₋₆alkyl, (4) —(CH₂)_(s)OH, (5)—(CH₂)_(s)SO₂C₁₋₆alkyl, (6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, (7)—(CH₂)_(s)C₃₋₆cycloalkyl, (8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH; Y is selected from: (1) —CH(OH)—, (2) —C(C₁₋₆alkyl)(OH)—,(3) —C[(CH₂)_(t)—C₃₋₆cycloalkyl](OH)—, (4) O, (5) S, and (6) SO₂,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH; Z is selected from: (1) hydrogen, (2) —C₁₋₆alkyl, (3)—(CH₂)_(s)—O—C₁₋₆alkyl, (4) —(CH₂)_(s)—OH, (5) —(CH₂)_(s)SO₂C₁₋₆alkyl,(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, (7)—(CH₂)_(s)C₃₋₆cycloalkyl, and (8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; m is0, 1, 2 or 3; n is 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3,provided that p+q is at least 2; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3; tis 0, 1, 2 or 3; u is 0, 1, 2 or 3; v is 0, 1, 2 or 3; and w is 0, 1, 2or
 3. 2. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein A is phenyl; B isselected from the group consisting of: (1) phenyl, and (2) pyridyl; R¹is selected from the group consisting of: (1) halogen, (2) —CN, (3)—C₁₋₆alkyl, (4) —(CH₂)_(r)—OC₁₋₆alkyl, (5) —(CH₂)_(r)—C₃₋₆cycloalkyl,and (6) —(CH₂)_(r)—O—(CH₂)_(r)—C₃₋₆cycloalkyl, wherein each CH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to four substituents selected from halogen,—C₁₋₆alkyl and —(CH₂)_(v)—C₃₋₆cycloalkyl; R² is halogen; R³ when presentis selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl,and (3) —(CH₂)—C₃₋₆cycloalkyl, wherein each C₁₋₆alkyl and C₃₋₆cycloalkylis unsubstituted or substituted with one to three substituents selectedfrom halogen; R⁴ is —OC₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with one, two, three or four substituents selected from R⁵;R⁵ is selected from the group consisting of: (1) —(CH₂)_(s)halogen, (2)—C₁₋₆alkyl, (3) —(CH₂)_(s)—O—C₁₋₆alkyl, (4) —(CH₂)_(s)OH, (5)—(CH₂)_(s)SO₂C₁₋₆alkyl, (6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, (7)—(CH₂)_(s)C₃₋₆cycloalkyl, (8) —(CH₂)_(r)—O—(CH₂)_(t)—C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH; Y is selected from: (1) —CH(OH)—, (2) —C(C₁₋₆alkyl)(OH)—,(3) —C [(CH₂)_(t)—C₃₋₆cycloalkyl](OH)—, (4) O, (5) S, and (6) SO₂,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen and(CH₂)_(w)OH; Z is selected from: (1) hydrogen, (2) —C₁₋₆alkyl, (3)—(CH₂)_(s)—O—C₁₋₆alkyl, (4) —(CH₂)_(s)—OH, (5) —(CH₂)_(s)SO₂C₁₋₆alkyl,(6) —(CH₂)_(s)SO₂—(CH₂)_(t)—C₃₋₆cycloalkyl, (7)—(CH₂)_(s)C₃₋₆cycloalkyl, and (8) —(CH₂)_(s)—O—(CH₂)_(t)—C₃₋₆cycloalkyl,wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; m is0, 1, 2 or 3; n is 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3,provided that p+q is at least 2; r is 0, 1, 2 or 3; s is 0, 1, 2 or 3; tis 0, 1, 2 or 3; u is 0, 1, 2 or 3; v is 0, 1, 2 or 3; and w is 0, 1, 2or
 3. 3. The compound of claim 1 of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein A is phenyl; B isselected from the group consisting of: (1) phenyl, and (2) pyridyl; R¹is selected from the group consisting of: (1) halogen, (2) —CN, (3)—C₁₋₆alkyl, (4) —OC₁₋₆alkyl, and (5) —C₃₋₆cycloalkyl, wherein each—C₁₋₆alkyl, —OC₁₋₆alkyl and —C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to four substituents selected from halogen; R² ishalogen; R³ is selected from the group consisting of: (1) halogen, (2)—C₁₋₆alkyl, and (3) —C₃₋₆ cycloalkyl, wherein each C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from halogen; R⁴ is —OC₁₋₆alkyl, wherein—C₁₋₆alkyl is unsubstituted or substituted with one, two, three or foursubstituents selected from R⁵; R⁵ is selected from the group consistingof: (1) —C₁₋₆alkyl, (2) —(CH₂)_(s)OH, (3) —(CH₂)_(s)SO₂C₁₋₆alkyl, (4)—(CH₂)_(s)halogen, (5) —(CH₂)_(s)OC₁₋₆alkyl, (6)—(CH₂)_(s)C₃₋₆cycloalkyl, and

wherein each CH₂, C₁₋₆alkyl and C₃₋₆cycloalkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; Y isselected from: (1) O, (2) S, and (3) SO₂; Z is selected from: (1)hydrogen, (2) —C₁₋₆alkyl, (3) —(CH₂)_(s)—O—C₁₋₆alkyl, (4) —(CH₂)_(s)—OH,and (5) —(CH₂)_(s)C₃₋₆cycloalkyl, wherein each CH₂, C₁₋₆alkyl andC₃₋₆cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from halogen; m is 0, 1, 2 or 3; n is 1 or 2; p is0, 1, 2 or 3; q is 0, 1, 2 or 3, provided that p+q is at least 2; and sis 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
 4. Thecompound according to claim 1 wherein A is:

or a pharmaceutically acceptable salt thereof.
 5. The compound accordingto claim 1 wherein A is

or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 1 wherein B is phenyl, wherein phenyl is unsubstituted orsubstituted with one, two or three substituents selected from R³; or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1 wherein R¹ is selected from the group consisting of: (1)halogen, and (2) —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with one to four substituents selected from halogen; or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1 wherein R¹ is —C₁₋₆alkyl, wherein each —C₁₋₆alkyl is substitutedwith one, two or three substituents selected from halogen; or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1 wherein R² is F; or a pharmaceutically acceptable salt thereof.10. The compound according to claim 1 wherein R³ when present isselected from the group consisting of: (1) halogen, and (2) —C₁₋₆alkyl,wherein each C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen; or a pharmaceutically acceptablesalt thereof.
 11. The compound according to claim 1 wherein R⁴ isOC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one substituentselected from R⁵; or a pharmaceutically acceptable salt thereof.
 12. Thecompound according to claim 1 wherein R⁵ is selected from the groupconsisting of: (1) —C₁₋₆alkyl, (2) —(CH₂)_(w)OH, (3)—(CH₂)_(s)SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen; or a pharmaceuticallyacceptable salt thereof.
 13. The compound according to claim 1 whereinR⁵ is selected from the group consisting of: (1) —C₁₋₆alkyl, (2) —OH,(3) —SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen; or a pharmaceuticallyacceptable salt thereof.
 14. The compound according to claim 1 wherein Zis selected from: (1) hydrogen, (2) —C₁₋₆alkyl, (3)—(CH₂)_(s)—O—C₁₋₆alkyl, and (4) —(CH₂)_(s)—OH, wherein each CH₂, andC₁₋₆alkyl is unsubstituted or substituted with one to three substituentsselected from halogen; or a pharmaceutically acceptable salt thereof.15. The compound according to claim 1 wherein R⁵ is selected from thegroup consisting of: (1) —C₁₋₆ alkyl, and (2) —(CH₂)_(s)OH, wherein eachCH₂ and C₁₋₆alkyl is unsubstituted or substituted with one to threesubstituents selected from halogen; or a pharmaceutically acceptablesalt thereof.
 16. The compound according to claim 1 wherein the absolutestereochemistry at the two stereogenic carbon centers is indicatedbelow:

or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 1 or 2 wherein: A is phenyl; B is phenyl or pyridyl;R¹ is selected from the group consisting of: (1) halogen, and (2)—C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted or substituted with oneto four substituents selected from halogen; R² is halogen; R³ whenpresent is selected from the group consisting of: (1) halogen, and (2)—C₁₋₆alkyl, wherein each C₁₋₆alkyl is unsubstituted or substituted withone to three substituents selected from halogen; R⁴ is OC₁₋₆alkyl,wherein —C₁₋₆alkyl is substituted with one substituent selected from R⁵;R⁵ is selected from the group consisting of: (1) —C₁₋₆alkyl, (2)—(CH₂)_(s)OH, (3) —(CH₂)_(s)SO₂C₁₋₆alkyl, and

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen; and Z is selected from: (1)hydrogen, (2) —C₁₋₆alkyl, (3) —(CH₂)_(s)—O—C₁₋₆alkyl, and (4)—(CH₂)_(s)—OH, wherein each CH₂, and C₁₋₆alkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; m is0, 1, 2 or 3; n is 1 or 2; p is 0, 1, 2 or 3; q is 0, 1, 2 or 3,provided that p+q is at least 2; and s is 0, 1, 2 or 3; or apharmaceutically acceptable salt thereof.
 18. The compound according toclaim 2 wherein: A is:

B is phenyl or pyridyl; R¹ is selected from the group consisting of: (1)halogen, and (2) —C₁₋₆alkyl, wherein —C₁₋₆alkyl is unsubstituted orsubstituted with one to four substituents selected from halogen; R² ishalogen; R³ when present is selected from the group consisting of: (1)halogen, and (2) —C₁₋₆alkyl, wherein each C₁₋₆alkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; R⁴ isOC₁₋₆alkyl, wherein —C₁₋₆alkyl is substituted with one substituentselected from R⁵; R⁵ is selected from the group consisting of: (1)—C₁₋₆alkyl, (2) —OH, (3) —SO₂C₁₋₆alkyl, and (4)

wherein each CH₂ and C₁₋₆alkyl is unsubstituted or substituted with oneto three substituents selected from halogen; Z is —(CH₂)_(r)—OH; m is 0,1, 2 or 3; and or a pharmaceutically acceptable salt thereof.
 19. Thecompound according to claim 2 wherein A is

B is phenyl; R¹ is —C₁₋₆alkyl, wherein each —C₁₋₆alkyl is substitutedwith one, two or three substituents selected from halogen; R² is F; R³when present is selected from the group consisting of: (1) halogen, and(2) —C₁₋₆alkyl, wherein each C₁₋₆alkyl is unsubstituted or substitutedwith one to three substituents selected from halogen; R⁴ is OC₁₋₆alkyl,wherein —C₁₋₆alkyl is substituted with one substituent selected from R⁵;R⁵ is selected from the group consisting of: (1) —C₁₋₆alkyl, and (2)—(CH₂)_(w)OH, wherein each CH₂ and C₁₋₆alkyl is unsubstituted orsubstituted with one to three substituents selected from halogen; m is0, 1, 2 or 3; and or a pharmaceutically acceptable salt thereof.
 20. Thecompound according to claim 18 selected from:

or a pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.22-24. (canceled)
 25. A method of treating or preventing a disorder,condition or disease that is responsive to the agonism of theG-protein-coupled receptor 40 in a patient in need thereof comprisingadministration of a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 26.A method of treating type 2 diabetes mellitus in a patient in need oftreatment comprising the administration to the patient of atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition comprising (1) a compound of claim 1 or a pharmaceuticallyacceptable salt thereof; (2) one or more compounds selected from thegroup consisting of: (a) PPAR gamma agonists and partial agonists; (b)biguanides; (c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (d)dipeptidyl peptidase IV (DP-IV) inhibitors; (e) insulin or an insulinmimetic; (f) sulfonylureas; (g) α-glucosidase inhibitors; (h) agentswhich improve a patient's lipid profile, said agents being selected fromthe group consisting of (i) HMG-CoA reductase inhibitors, (ii) bile acidsequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof,(iv) PPARa agonists, (v) cholesterol absorption inhibitors, (vi) acylCoA: cholesterol acyltransferase (ACAT) inhibitors, (vii) CETPinhibitors, and (viii) phenolic anti-oxidants; (i) PPARα/γ dualagonists, (j) PPARδ agonists, (k) antiobesity compounds, (l) ileal bileacid transporter inhibitors; (m) anti-inflammatory agents; (n) glucagonreceptor antagonists; (o) GLP-1; (p) GIP-1; (q) GLP-1 analogs; (r) HSD-1inhibitors; (s) SGLT 1 inhibitors; and (t) SGLT 2 inhibitors; and (3) apharmaceutically acceptable carrier.
 28. A pharmaceutical compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a compound selected from simvastatin,ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.29. A method of treating type 2 diabetes mellitus in a patient in needof treatment comprising the administration to the patient of atherapeutically effective amount of a compound of claim 2, or apharmaceutically acceptable salt thereof.